- Email: [email protected]
Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series
Original Investigation
Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series Yuan Zhang, Xiaomei Li, Dandan Liang, Feng Xu, Shaoshan Liang, Xiaodong Zhu, Nanjun Zheng, Xianghua Huang, Zhihong Liu, and Caihong Zeng Rationale & Objective: Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. Study Design: Case series. Setting & Participants: 25 patients with biopsyproven HCDD were studied retrospectively. Results: 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2 mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3
was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (g1, 13; g2, 2; g3, 6; g4, 2; g1 and g4, 1; and g2 and g4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy.
Correspondence to C. Zeng ([email protected]) Am J Kidney Dis. XX(XX):18. Published online Month X, XXXX. doi: 10.1053/ j.ajkd.2019.08.013
© 2019 by the National Kidney Foundation, Inc.
Limitations: Retrospective study, single-center experience. Conclusions: In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.
H
eavy chain deposition disease (HCDD) is a rare form of monoclonal immunoglobulin deposition disease, with poor outcomes historically.1 Since 1992, when Tubbs et al2 reported the first 2 cases of HCDD, only about 70 cases have been reported. HCDD is defined by the presence of tissue deposits of truncated monoclonal immunoglobulin heavy chains, most frequently with heavy chain from immunoglobulin G (IgG; g-HCDD) and occasionally IgA (α-HCDD), IgM (μ-HCDD), or IgD (δ-HCDD).3 Clinical manifestations include hypertension, progressive loss of kidney function, anemia, hypocomplementemia, nephrotic-range proteinuria, and microhematuria.4 Until now, limited data were available on HCDD in non-white populations. In our center from 2003 to 2014, the frequency of monoclonal immunoglobulin deposition disease has tripled.5 It is estimated that HCDD will be diagnosed in growing numbers of people in the next decade. We previously published a case series of light chain deposition disease (LCDD).6 In this report, we retrospectively analyzed 25 Chinese patients with HCDD to obtain a better understanding of this disease. Methods Patients and Clinical Data All native kidney biopsies (49,622 cases) were retrospectively reviewed in the Jinling Hospital Department of AJKD Vol XX | Iss XX | Month 2019
Complete author and article information provided before references.
Nephrology, Nanjing Medical University, (Nanjing, China) from 2008 to 2018. Inclusion criteria were as follows4: (1) variable mesangial expansion, membranoproliferative appearance, or nodular sclerosis; (2) monoclonal heavy chain staining in mesangium and along glomerular (GBM) and tubular basement membranes (TBM) with linear appearance; and (3) punctate, amorphous, or ground pepper–like deposits along the inner aspect of the GBMs and outer aspect of the TBMs on electron microscopy. A total of 25 patients with HCDD were enrolled in this study. Since 2000 in our hospital, informed consent was obtained from all patients who underwent kidney biopsies for establishing a biobank (including blood and urine samples) for any future retrospective studies. Creation of the biobank was approved by the Ethics Committee of Jinling Hospital (2017NZKY-013-01). This study was approved by the Ethics Committee of Jinling Hospital (2019NZKYKS-004-01) and was conducted in compliance with the Declaration of Helsinki. Demographic information, clinical data at the time of biopsy, and treatment and follow-up information were collected from patient medical records. A standard definition of multiple myeloma was applied.7 Clinical manifestations were defined as described previously.6 In our study of LCDD, we defined hematologic complete response as normalization of serum free light chain 1
Original Investigation (FLC) ratio, hematologic partial response as >50% decrease in FLCs from baseline, and hematologic nonresponse as ≤50% decrease in FLCs from baseline.6 As was done in a previous case series,8 hematologic complete response for heavy chain was defined by the disappearance of the circulating truncated monoclonal heavy chain by serum immunofixation. Improvement in kidney function was defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 or (2) ≥50% decrease (by at least 0.5 g) in 24-hour urine protein excretion in the absence of a reduction in estimated glomerular filtration rate ≥ 25% or an increase in serum creatinine level ≥ 0.5 mg/dL.6,9 Pathology Studies All kidney biopsies were processed using the standard light microscopy, immunofluorescence, and electron microscopy techniques.6,10 Tubular atrophy and interstitial fibrosis were scored semiquantitatively based on the percentage of the tubulointerstitial compartment affected and recorded as 0%, 1% to 25% (mild), 26% to 50% (moderate), or >50% (marked). Immunofluorescence was performed on cryosections (4 μm) using fluorescein isothiocyanate–conjugated polyclonal antibodies to IgG (IgG1-4), IgM, IgA, C3, C1q, and κ and λ light chains (Dako Corp). Ultrastructural evaluation was performed using a Hitachi 7500 transmission electron microscope. Statistical Methods Analysis was performed using SPSS, version 25.0, statistical software package (SPSS Inc). Two-sided P < 0.05 was considered statistically significant. Data are expressed as mean ± standard deviation or median with interquartile range for continuous variables and number with percentage for categorical variables. Survival analysis was performed by univariate survival analysis and Kaplan-Meier curves.
Results Demographics and Clinical Characteristics We retrospectively identified 25 patients with HCDD who had undergone kidney biopsy in the past 10 years, corresponding to 0.05% of biopsies. We also diagnosed 71 cases of LCDD (0.143%) and 8 cases of light and heavy chain deposition disease (0.016%). As shown in Table 1, of the patients with HCDD, 11 (44%) were women. Average age was 50.3 ± 9.6 years at the time of kidney biopsy. Median time from initial presentation to the time of biopsy was 8.0 months. Median serum creatinine level was 1.6 mg/dL and 68% of patients had serum creatinine levels > 1.2 mg/dL. Baseline average estimated glomerular filtration rate was 50.4 ± 28.0 mL/min/1.73 m2. Other presenting symptoms included hypertension (76%), peripheral edema (96%), nephrotic-range proteinuria (56%), microscopic hematuria (80%), and nephrotic syndrome (40%). None had macroscopic hematuria or extrarenal manifestations. 2
Table 1. Demographic and Clinical Characteristics of 25 Chinese Patients With HCDD at the Time of Kidney Biopsy Parameter Female sex Age at biopsy, y Time from initial presentation to kidney biopsy, mo Hypertension Edema Serum creatinine, mg/dL Serum creatinine > 1.2 mg/dL eGFR, mL/min/1.73 m2 Serum albumin, g/L Hypoalbuminemia (serum albumin < 35 g/L) Urine protein, g/24 h Nephrotic-range proteinuria, ≥3.5 g/24 h Microscopic hematuria Macroscopic hematuria Nephrotic syndrome Extrarenal manifestations Dialysis at biopsy
Value 11 (44%) 50.3 ± 9.6 8.0 (1-60) 19 (76%) 24 (96%) 1.6 (0.9-6.5) 17 (68%) 50.4 ± 28.0 29.6 ± 5.8 21 (84%) 4.0 ± 2.5 14 (56%) 20 (80%) 0 (0%) 10 (40%) 0 (0%) 0 (0%)
Note: Values for continuous data given as mean ± standard deviation or median (range); for categorical data, as count (percentage). Abbreviations: eGFR, estimated glomerular filtration rate; HCDD, heavy chain deposition disease.
Hematologic Characteristics Average hemoglobin level was 9.8 ± 2.0 g/dL, with anemia present in 84% of patients. Serum immunofixation electrophoresis was performed in 21 patients. Of the 10 (48%) patients who had detectable monoclonal protein, most (n = 8) had IgG λ light chain. Elevated FLC ratio (κ:λ > 1.65) was observed in 12 of 25 (48%) patients, and 3 of 25 (12%) had an FLC ratio < 0.26. Interestingly, at baseline, 2 of 25 (8%), 7 of 25 (28%), and 10 of 25 (40%) had κ FLC level, λ FLC level, and FLC ratio in the reference range, respectively. At the end of follow-up, the corresponding proportions were 2 of 13 (15%), 5 of 13 (38%), and 7 of 13 (54%) (Table S1). In total, 17 of 25 (68%) and 6 of 25 (24%) patients had hypocomplementemia of C3 and C4, respectively. Twentytwo patients underwent bone marrow biopsy. One patient had multiple myeloma diagnosed, with 13.5% plasma cells in bone marrow, serum monoclonal IgG λ light chain by serum immunofixation electrophoresis, and hemoglobin level of 9.1 g/L. Urine Bence-Jones protein test was negative in all 13 patients in whom it was performed (Table 2). Pathologic Characteristics Light Microscopy All cases were characterized by nodular mesangial sclerosis (Fig 1A and B). There was an average of 25.6 ± 7.6 glomeruli per biopsy specimen. Global sclerosis was found in 14 (56%) cases, with the percentage of globally sclerotic glomeruli ranging from 3% to 48%. Segmental sclerosis was noted in only 2 cases (affecting 3% and 10% of glomeruli). Fibrocellular crescents were present in 6 AJKD Vol XX | Iss XX | Month 2019
Original Investigation Table 2. Hematologic Characteristics at the Time of Kidney Biopsy Parameter Hemoglobin, g/dLa Anemia Monoclonal protein by sIFE IgG κ light chain IgA κ light chain IgG λ light chain Abnormal FLC ratio (<0.26 or >1.65) FLC ratio < 0.26 FLC ratio > 1.65 Median FLC concentration κ, mg/L λ, mg/L Hypocomplementemia C3 < 0.8 g/L C4 < 0.1 g/L Diagnosis of multiple myeloma ≥10% plasma cells on bone marrow biopsy
Value 9.8 ± 2.0 21/25 (84%) 10/21 (48%) 1 1 8 15/25 (60%) 3 12 66 52 17/25 (68%) 6/25 (24%) 1/25 (4%) 21/22 (95%)
Abbreviations: FLC, free light chain; IgG, immunoglobulin G; sIFE, serum immunofixation electrophoresis. a Mean ± standard deviation.
(24%) patients, with the percentage of fibrocellular crescents per biopsy ranging from 4% to 20%. Mesangial nodules were generally periodic acid–Schiff–positive and poorly argyrophilic (Fig 1A and C). Ten (40%) patients showed numerous fuchsinophilic deposits in the mesangial and subendothelial areas. Partial mesangiolysis was also observed in 5 cases (Fig 1B). However, there was no diffuse thickening of GBMs. Tubular atrophy and interstitial fibrosis were present in 22 (88%) patients and were marked in 5 (20%), moderate in 7 (28%), and mild in 10 (40%). TBMs were thickened and tortuous. Vascular lesions were observed in 23 (92%) cases, which were characterized by hyaline degeneration in arterioles and intimal thickening in interlobular arteries (Table 3). Immunofluorescence
All cases demonstrated linear deposits of monoclonal IgG along GBMs and TBMs (Fig 1D), but were negative for IgA, IgM, and κ and λ light chains. IgG subclass staining showed monotypic g heavy chains in all patients (g1, 13; g2, 2; g3, 6; g4, 2; g1 and g4, 1; and g2 and g4, 1). Seventeen patients had complement C3 and C1q deposits of the same pattern and intensity as IgG deposits. Two cases had C3 only, and 3 cases had no complement staining. Monotypic heavy chain staining was present in GBMs in all 25 cases, including the mesangium in 15 (60%), and also along TBMs in 76% of cases. Staining was also observed in Bowman capsule in 7 (28%) and arterial walls in 8 (32%) cases (Table 3). Electron Microscopy
Continuous (70%) or intermittent (30%) deposition of fine granular electron-dense material along the inner AJKD Vol XX | Iss XX | Month 2019
aspect of GBMs and outer aspect of TBMs was observed (Fig 1E and F). Deposits were also seen in the expanded mesangium in 64% of patients (Table 3). There was no organized substructure identified in deposits in any case. Eight (32%) patients showed injury to endothelial cells, presenting as widening of the subendothelial area, fibrin deposition, and exfoliation of endothelial cells. Endocapillary hypercellularity with neutrophil infiltration was present in 2 (10%) cases. In some areas, tubular cells were exfoliated from the TBMs, leaving the TBMs denuded. One patient had electron-dense deposits in a peritubular capillary wall. Extensive foot-process fusion (>50%) was observed in 9 of 22 patients (41%). Hypocomplementemia and g Isotypes Hypocomplementemia of C3 was more prevalent in g3HCDD (6 of 6 [100%]), followed by g1-HCDD (10 of 13 [77%]) and g2-HCDD (1 of 2 [50%]). Moreover, the patient with g1 and g4 HCDD also presented with a low C3 level. Neither of the 2 patients with g4-HCDD was found to have a reduced C3 level. A low C4 level was found only in g1-HCDD and g3-HCDD. Treatment and Outcomes Clinical follow-up was available for 20 of 25 (80%) patients. Average follow-up time was 40.1 ± 29.2 months after biopsy. Chemotherapy included thalidomide and dexamethasone (TD) in 8 patients; vincristine, Adriamycin, and dexamethasone (VAD) in 1; BD (bortezomib and dexamethasone) + TD in 2, VAD + BD in 1, and BD + TD + cyclophosphamide in 1. No one received an autologous stem cell transplant after chemotherapy. At last follow-up, in terms of light chain hematologic response, 4 of 10 (40%) patients were in complete response, 2 of 10 (20%) were in partial response, and 4 of 10 (40%) were in nonresponse. For heavy chain hematologic response, 1 of 20 (5%) was in complete response. For kidney function, 13 of 20 (65%) experienced an improvement and only 2 of 20 (10%) experienced a worsening (Tables 4 and S1). Seven patients (7 of 20 [35%]) did not receive chemotherapy before or after kidney biopsy, and 5 (71%) of these progressed to kidney failure, including 1 patient who died. Thirteen patients were treated with some form of chemotherapy; none progressed to kidney failure. Moreover, a higher percentage of patients in the chemotherapy group had kidney function improvement than that of the no-chemotherapy group (P = 0.001). For kidney failure, a lower percentage of patients in the chemotherapy group reached this end point than that of the nochemotherapy group (P = 0.001; Table 5). Number of globally sclerotic glomeruli was associated with risk for kidney failure on univariate analysis (P = 0.04; hazard ratio, 1.364; 95% confidence interval, 1.010-1.469). Other clinical and histopathologic parameters did not correlate with kidney survival. 3
Original Investigation
Figure 1. Heavy chain disposition disease with typical nodular glomerulosclerosis and ultrastructural features. (A) Increased mesangial matrix in the glomerulus, nodule formation (periodic acid–Schiff [PAS]; original magnification, ×200). (B) Partial mesangial dissolution (PAS; original magnification, ×400). (C) Nodules were poorly argyrophilic and containing capillary microaneurysms (periodic acid-silver metheramine; original magnification, ×200). (D) Immunofluorescence identified linear deposits of immunoglobulin G along the glomerular (GBMs) and tubular basement membranes (TBMs) (original magnification, ×200). (E, F) Finely granular or “powdery” electron-dense deposits were detected along the (E) inner aspect of GBMs (electron microscopy; original magnification, ×10,000) and (F) outer aspect of the TBMs (electron microscopy; original magnification, ×23,000).
According to the Kaplan-Meier survival analysis, kidney survival was remarkably poorer in the group with no chemotherapy (log-rank test P = 0.003, Gehan-BreslowWilcoxon test P = 0.005), but there were no significant differences among the different regimens of chemotherapy. Mean kidney survival of the chemotherapy group was 36.0 months, double the value of the nochemotherapy group (19.0 months; Fig 2).
4
Discussion In this study, we analyzed clinicopathologic features and outcomes of 25 patients with HCDD. To our knowledge, this is the largest experience of HCDD in the Chinese population; all prior series predominantly involved white patients.8,11,12 In our case series, clinical manifestations were similar to those in prior studies.8,12,13 However, we observed an AJKD Vol XX | Iss XX | Month 2019
Original Investigation Table 3. Pathologic Characteristics Parameter Light microscopy No. of glomeruli per biopsya Biopsies with globally sclerotic glomeruli Biopsies with segmental sclerosis Biopsies with fibrocellular crescent Biopsies with nodular mesangial sclerosis Biopsies with tubular atrophy and interstitial fibrosis Mild Moderate Marked Biopsies with vascular lesions Immunofluorescence Heavy chain g1 g2 g3 g4 g1 and g4 g2 and g4 Deposition of C3 Deposition of C1q Monoclonal deposits TBMs GBMs Mesangium Bowman capsule Vascular wall Electron microscopy TBM deposits GBM deposits Mesangium deposits Extensive foot-process fusion (>50%)
Value 25.6 ± 7.6 14/25 (56%) 2/25 (8%) 6/25 (24%) 25/25 (100%) 22/25 (88%) 10/25 (40%) 7/25 (28%) 5/25 (20%) 23/25 (92%)
13 2 6 2 1 1 19/25 (76%) 17/25 (68%) 19/25 (76%) 25/25 (100%) 15/25 (60%) 7/25 (28%) 8/25 (32%) 25/25 (100%) 22/22 (100%)b 14/22 (64%)b 9/22 (41%)b
Abbreviations: GBM, glomerular basement membrane; TBM, tubular basement membrane. a Mean ± standard deviation. b Specimens from 3 patients had no glomeruli observable with electron microscopy.
incidence (0.05%) lower than that reported by others.12 Compared with the study of Bridoux et al,8 patients in our study were younger, had less severely decreased kidney function, and had less frequently received chemotherapy. Our cohort had only g heavy chain deposition, while in study of Bridoux et al,8 2 classes of heavy chains (g, 15; α, 3) were found. These differences suggest that age of onset and severity level may be lower in Chinese versus white populations. In our series, no one had a diagnosis of extrarenal disease, compared with Bridoux et al,8 who reported that 3 patients had systemic manifestations, including liver cholestasis, nodular goiter, interstitial pneumonia, purpuric skin lesions, and ulcerative hemorrhagic esophagitis. In 2012, the International Kidney and Monoclonal Gammopathy Research Group recognized HCDD as a monoclonal gammopathy of renal significance–associated lesion.14 The monoclonal protein is due to an underlying AJKD Vol XX | Iss XX | Month 2019
plasma cell dyscrasia. Besides renal lesions, hematologic manifestations in our patients with HCDD were also remarkable. Anemia was present in 84% of our patients, but only 1 individual had severe anemia. Anemia may not always correlate with kidney function15 because it was also observed in individuals without apparent reduction in kidney function. In addition, the percentage of patients with a positive result on serum immunofixation electrophoresis was significantly lower in our study (48%) than that reported by Bridoux et al8 (80%). Three types of monoclonal immunoglobulin (ie, IgG κ, IgA κ, and IgG λ light chains) were noted in our study on serum immunofixation electrophoresis. In the Bridoux et al8 case series, the authors also observed IgA λ light chain. Moreover, only g-HCDD cases were observed in our cohort, while others have reported α-HCDD, μ-HCDD, and δ-HCDD in white patients. The type of FLC is often consistent with the type of serum abnormal monoclonal band. Ten of 15 patients with abnormal FLC ratios had monoclonal protein. The abnormal FLC ratio of the 10 patients is consistent with the monoclonal protein. Patients without monoclonal protein had abnormal FLC ratios manifested as excess κ light chain. Interestingly, 1 patient showed tissue deposition of IgG3, but serum immunofixation electrophoresis revealed monoclonal IgA κ light chain. It is unclear why only g heavy chains were seen in our cohort. A multicenter study is needed to collect more cases to answer this question in China. IgA monoclonal gammopathy does not appear to be less common in China versus other countries.16,17 The possibility of misdiagnosis is relatively small because electron microscopy is performed in every native biopsy case in our center. Using biopsies from the same period, we diagnosed light and heavy chain deposition disease in 8 patients (IgAλ, 2; IgG1λ, 1; IgG2λ, 1; IgG2κ, 1; IgG1κ, 2; and IgG3κ, 1). In our study, 2 patients had concurrent deposition of 2 types of IgG (IgG1 and IgG4, and IgG2 and IgG4, respectively; 1 of these 2 patients was previously reported by Yin et al18). The reason for the concomitant deposition of 2 subclasses of IgG is unclear. We observed that even when FLC concentration is within the reference range, the ratio may be abnormal. Likewise, even when FLC concentration is out of the reference range, the ratio may still be normal (Table S1). Nasr et al12 reported that among 4 patients with HCDD who underwent FLC testing, all had abnormal FLC ratios. The reason for this finding may be that the abnormal heavy chain causes the light chain to fail to assemble with it, resulting in an excess of the light chain, or it may be related to different types of light chain due to different sites of gene mutation19 that cannot be assembled with the normal heavy chain. However, because free heavy chains have a high affinity for tissues and are not concentrated in the circulation,20 immunofixation electrophoresis or assaying FLC ratio cannot be the confirmatory test. 5
Original Investigation Table 4. Treatment, Response, and Kidney Outcomes Hematologic Response Pt 1 2 3 5 8 9 10 11 12 13 14 15 16 17 18 19 22 23 24 25
Chemotherapy None TD TD TD None TD BD + TD + BD TD None TD TD BD + TD TD None None BD + TD + CTX VAD + BD VAD None None
Therapy Cycles
Light Chain CR
Heavy Chain
2 7 6 2+1+1 4 22 17 1 + 24 29
Always normal Always normal PR NR CR CR NR CR
2 + 19 + 6 4+2 4
PR NR NR
CR
Always normal
Kidney Function Outcomea Kidney failure Worsening Improved Improved Kidney failure Improved Improved Improved Kidney failure Improved Improved Improved Improved Improved Kidney failure Improved Improved Improved Kidney failure Worsening
Death No No No No Yes No No No No No No No No No No No No No No No
Note: Patients 4, 6, 7, 20, and 21 had no follow-up. Abbreviations: BD, bortezomib and dexamethasone; CR, complete response; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; NA, not available; NR, no response; PR, partial response; Scr, serum creatinine; TD, thalidomide and dexamethasone; VAD, vincristine, Adriamycin, and dexamethasone. a Improved kidney function defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with eGFR ≥ 60 mL/min/1.73 m2 or (2) a ≥50% decrease (at least 0.5 g/ 24 h) in 24-hour urine protein excretion in the absence of a reduction in eGFR ≥ 25% or an increase in Scr level ≥ 0.5 mg/dL. Worsening kidney function was defined as >50% increase in Scr level from baseline but <6.0 mg/dl; kidney failure was defined as Scr level > 6.0 mg/dL or being dependent on kidney replacement therapy.
Among patients with hypocomplementemia, all had codeposition of complement components C3 and C1q, with most heavy chains being of IgG1 (9 of 17) and IgG3 (6 of 17) subclass, and the others being of the IgG2 (1 of 17) or IgG1 and IgG4 (1 of 17) subclass. These findings suggest that these heavy chains are sufficient to act on the classical pathway locally and systemically. Among patients with normal complement levels, 3 (all IgG1) had codeposition of C3 and C1q, suggesting that only the local complement classical pathway was active. One possible explanation is that structural differences in heavy chain subtypes may elicit different complement activation pathways. Two IgG4 cases had C3 only without C1q deposition, suggesting that perhaps the lectin pathway and/or alternative pathway were involved. Also, 3 cases (IgG2 and IgG4, IgG2, and IgG1) had no C3 and C1q deposition. Whether local and/or systemic activation of the classical complement pathway relates to the pathogenesis of HCDD continues to be unclear.8 Normalization of complement levels has been reported to occur during treatment.21,22 Future studies are needed to determine whether serum complement levels could be used as a biomarker of treatment response. Most (95%) glomeruli exhibited diffuse nodular mesangial sclerosis, resulting in an increase in glomerular volume. In our previous LCDD report, glomerular nodules occurred in 80%, which was also significantly higher than that
6
reported by others in white patients.6 These observations suggest that HCDD and LCDD nodules in Chinese people may be more obvious. Comparing the renal pathologic Table 5. Clinical Outcome According to Chemotherapy Treatment Chemotherapy
Improved kidney functiona Worsening kidney functionb Progression to kidney failurec Patient deaths Kidney survival, mod Patient survival, mod
Total (n = 20) 13
Yes (n = 13) 12
No (n = 7) 1
P 0.001
2
1
1
0.9
5
0
5
0.001
1 31.5 (1-118) 32.0 (1-119)
0 36.0 (4-74) 27.0 (1-119)
1 19.0 (1-118) 36.0 (4-77)
0.4 0.3 0.6
Abbreviations: eGFR, estimated glomerular filtration rate; Scr, serum creatinine. a Defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with eGFR ≥ 60 mL/min/1.73 m2 or (2) a ≥50% decrease (at least 0.5 g/24 h) in 24hour urine protein excretion in the absence of a reduction in eGFR ≥ 25% or an increase in Scr level ≥ 0.5 mg/dL. b Worsening kidney function was defined as >50% increase in Scr level from baseline but <6.0 mg/dL. c Kidney failure defined as Scr level > 6.0 mg/dL or being dependent on kidney replacement therapy. d Values expressed as mean (range).
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Original Investigation Supplementary Material Supplementary File (PDF) Table S1: Serum immunofixation electrophoresis and FLC findings in patients with HCDD.
Article Information Authors’ Full Names and Academic Degrees: Yuan Zhang, MD, Xiaomei Li, MD, Dandan Liang, MD, Feng Xu, MD, Shaoshan Liang, PhD, Xiaodong Zhu, MD, Nanjun Zheng, BS, Xianghua Huang, PhD, Zhihong Liu, MD, and Caihong Zeng, PhD. Authors’ Affiliation: Jinling Hospital Department of Nephrology, Nanjing Medical University, Nanjing, PR, China. Address for Correspondence: Caihong Zeng, PhD, Jinling Hospital Department of Nephrology, Nanjing Medical University, Nanjing, Jiangsu 210002, China. E-mail: [email protected]
Figure 2. Kaplan-Meier renal survival analysis, comparing patients with chemotherapy or not.
features of HCDD identified in our study and in the study by Bridoux et al,8 no statistical differences were found. In tubular atrophy/interstitial fibrosis, mild lesions accounted for the majority of cases in our cohort, while in Bridoux et al,7 moderate lesions accounted for the majority. Studies of monoclonal immunoglobulin deposition disease have demonstrated that lower initial kidney function is a predictive factor for progression to kidney failure.23 However, in our study, initial serum creatinine level did not predict the outcome of the disease. It may be because HCDD was found at a very early stage and responded well to chemotherapy or because the number of cases was too small to show statistical differences. Early diagnosis and treatment with BD appear to be important to preserve kidney function.8 Patients who received chemotherapy had a better prognosis than those who did not (P < 0.05). Although different chemotherapy regimens were used, all treated patients also had improved kidney function, and no treated patient developed kidney failure or died during chemotherapy treatment. No patients underwent stem cell transplantation in our center, so we were unable to judge the effect. Historically, the renal prognosis for patients with HCDD has been poor: 36% to 50% require hemodialysis within 1 year and 10% die within a mean duration of 12 to 76 months.23 In our study, outcomes appeared to be better than prior reports of white patients. We found that the kidney failure incidence within 1 year was 12%, and 5% died during follow-up. However, in our study of LCDD, 15 (34%)6 patients had stable or improved kidney function, significantly lower than HCDD (65%). In a case series at a single center in China, we found that HCDD in our patients presented exclusively with deposition of heavy chains of IgG class. Most individuals treated with chemotherapy could achieve improved kidney function, and adequate treatment for HCDD should be considered, especially for those in an early stage of the disease.
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Authors’ Contributions: Research idea and study design: YZ, CZ; data acquisition: YZ, XL; data analysis and interpretation: YZ, CZ, DL, FX, SL; statistical analysis: YZ; supervision or mentorship: CZ, DL, FX, SL, XZ, NZ, XH, ZL. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Support: This research was supported by National Key R&D Program of China (2016YFC0901202), which had a role in study design and data collection; and National Natural Science Foundation of China (No. 81570644), which had a role in analysis and reporting. Financial Disclosure: The authors declare that they have no other relevant financial interests. Acknowledgements: We are grateful to Prof Xin Jin (Joseph) Zhou for revising the manuscript. Peer Review: Received February 13, 2019. Evaluated by 2 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form August 4, 2019.
References 1. Patel K, Dillon JJ, Leung N, et al. Use of bortezomib in heavychain deposition disease: a report of 3 cases. Am J Kidney Dis. 2014;64(1):123-127. 2. Tubbs RR, Berkley V, Valenzuela R, et al. Pseudo-gamma heavy chain (IgG4 lambda) deposition disease. Mod Pathol. 1992;5(2):185-190. 3. Royal V, Quint P, Leblanc M, et al. IgD heavy-chain deposition disease: detection by laser microdissection and mass spectrometry. J Am Soc Nephrol. 2015;26(4):784-790. 4. Fogo AB, Lusco MA, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: heavy chain deposition disease. Am J Kidney Dis. 2016;67(3):e11-e12. 5. Hou JH, Zhu HX, Zhou ML, et al. Changes in the spectrum of kidney diseases: an analysis of 40,759 biopsy-proven cases from 2003 to 2014 in China. Kidney Dis (Basel). 2018;4(1): 10-19. 6. Li XM, Rui HC, Liang DD, et al. Clinicopathological characteristics and outcomes of light chain deposition disease: an analysis of 48 patients in a single Chinese center. Ann Hematol. 2016;95(6):901-909. 7. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548.
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Original Investigation 8. Bridoux F, Javaugue V, Bender S, et al. Unravelling the immunopathological mechanisms of heavy chain deposition disease with implications for clinical management. Kidney Int. 2017;91(2):423-434. 9. Cohen C, Royer B, Javaugue V, et al. Bortezomib produces high hematological response rates with prolonged renal survival in monoclonal immunoglobulin deposition disease. Kidney Int. 2015;88(5):1135-1143. 10. Hemminger J, Nadasdy G, Satoskar A, Brodsky SV, Nadasdy T. IgG subclass staining in routine renal biopsy material. Am J Surg Pathol. 2016;40(5):617-626. 11. Alexander MP, Nasr SH, Watson DC, M endez GP, Rennke HG. Renal crescentic alpha heavy chain deposition disease: a report of 3 cases and review of the literature. Am J Kidney Dis. 2011;58(4): 621-625. 12. Nasr SH, Valeri AM, Cornell LD, et al. Renal monoclonal immunoglobulin deposition disease: a report of 64 patients from a single institution. Clin J Am Soc Nephrol. 2012;7(2):231-239. 13. Katsuno T, Mizuno S, Mabuchi M, Tsuboi N, Komatsuda A, Maruyama S. Long-term renal survival of g3-heavy chain deposition disease: a case report. BMC Nephrol. 2017;18(1):239. 14. Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019;15(1):45-59. 15. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12(7):1482-1492.
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16. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13):1362-1369. 17. Ma L, Xu S, Qu J, et al. Monoclonal gammopathy of undetermined significance in Chinese population: a prospective epidemiological study. Hematol Oncol. 2019;37(1): 75-79. 18. Yin G, Wu Y, Zeng CH, Chen HP, Liu ZH. A unique case of gheavy chain deposition disease characterized by concomitant deposition of g2 and g4 subclasses. Intern Med. 2014;53(22): 2615-2618. 19. Bender S, Ayala MV, Javaugue V, et al. Comprehensive molecular characterization of a heavy chain deposition disease case. Haematologica. 2018;103(11):e557-e560. 20. Moulin B, Deret S, Mariette X, et al. Nodular glomerulosclerosis with deposition of monoclonal immunoglobulin heavy chains lacking C(H)1. J Am Soc Nephrol. 1999;10(3):519528. 21. Soma J, Sato K, Sakuma T, et al. Immunoglobulin gamma3heavy-chain deposition disease: report of a case and relationship with hypocomplementemia. Am J Kidney Dis. 2004;43(1): E10-E16. 22. Soma J, Tsuchiya Y, Sakuma T, Sato H. Clinical remission and histopathological resolution of nodular lesions in a patient with gamma3 heavy-chain deposition disease. Clin Nephrol. 2008;69(5):383-386. 23. Oe Y, Soma J, Sato H, Ito S. Heavy chain deposition disease: an overview. Clin Exp Nephrol. 2013;17(6):771-778.
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Heavy Chain Deposition Disease: Clinicopathologic Characteristics of a Chinese Case Series Yuan Zhang, Xiaomei Li, Dandan Liang, Feng Xu, Shaoshan Liang, Xiaodong Zhu, Nanjun Zheng, Xianghua Huang, Zhihong Liu, and Caihong Zeng Rationale & Objective: Heavy chain deposition disease (HCDD) is a rare consequence of monoclonal immunoglobulin deposition disease that has not been well characterized in non-white populations. To explore the clinicopathologic characteristics and outcomes of HCDD in Chinese individuals, we report on a case series assembled in a single center in China. Study Design: Case series. Setting & Participants: 25 patients with biopsyproven HCDD were studied retrospectively. Results: 14 men and 11 women with an average age of 50.3 years were studied. The patients presented with hypertension (76%), edema (96%), anemia (84%), serum creatinine level > 1.2 mg/dL (68%), nephrotic-range proteinuria (56%), and microscopic hematuria (80%). One (4%) patient had multiple myeloma diagnosed. Serum immunofixation electrophoresis showed that 10 of 21 (48%) patients were positive for monoclonal immunoglobulin. Hypocomplementemia of C3
was found in 68% of patients. Nodular mesangial sclerosis was identified in all patients by using light microscopy. Using immunofluorescence, all 25 patients had deposition of heavy chains of immunoglobulin G class (g1, 13; g2, 2; g3, 6; g4, 2; g1 and g4, 1; and g2 and g4, 1). During an average of 40.1 months of follow-up of 20 patients, 65% had improved kidney function, 10% had worsening kidney function, and 25% progressed to kidney failure. Mean values for kidney and patient survival were 37.8 and 40.1 months, respectively. Kidney survival was higher among patients who received chemotherapy.
Correspondence to C. Zeng ([email protected]) Am J Kidney Dis. XX(XX):18. Published online Month X, XXXX. doi: 10.1053/ j.ajkd.2019.08.013
© 2019 by the National Kidney Foundation, Inc.
Limitations: Retrospective study, single-center experience. Conclusions: In this case series of HCDD in a single center in China, the heavy chain deposits seen in the kidney biopies of all individuals were of immunoglobulin G class. Chemotherapy improved kidney function, especially among individuals in an early stage of the disease.
H
eavy chain deposition disease (HCDD) is a rare form of monoclonal immunoglobulin deposition disease, with poor outcomes historically.1 Since 1992, when Tubbs et al2 reported the first 2 cases of HCDD, only about 70 cases have been reported. HCDD is defined by the presence of tissue deposits of truncated monoclonal immunoglobulin heavy chains, most frequently with heavy chain from immunoglobulin G (IgG; g-HCDD) and occasionally IgA (α-HCDD), IgM (μ-HCDD), or IgD (δ-HCDD).3 Clinical manifestations include hypertension, progressive loss of kidney function, anemia, hypocomplementemia, nephrotic-range proteinuria, and microhematuria.4 Until now, limited data were available on HCDD in non-white populations. In our center from 2003 to 2014, the frequency of monoclonal immunoglobulin deposition disease has tripled.5 It is estimated that HCDD will be diagnosed in growing numbers of people in the next decade. We previously published a case series of light chain deposition disease (LCDD).6 In this report, we retrospectively analyzed 25 Chinese patients with HCDD to obtain a better understanding of this disease. Methods Patients and Clinical Data All native kidney biopsies (49,622 cases) were retrospectively reviewed in the Jinling Hospital Department of AJKD Vol XX | Iss XX | Month 2019
Complete author and article information provided before references.
Nephrology, Nanjing Medical University, (Nanjing, China) from 2008 to 2018. Inclusion criteria were as follows4: (1) variable mesangial expansion, membranoproliferative appearance, or nodular sclerosis; (2) monoclonal heavy chain staining in mesangium and along glomerular (GBM) and tubular basement membranes (TBM) with linear appearance; and (3) punctate, amorphous, or ground pepper–like deposits along the inner aspect of the GBMs and outer aspect of the TBMs on electron microscopy. A total of 25 patients with HCDD were enrolled in this study. Since 2000 in our hospital, informed consent was obtained from all patients who underwent kidney biopsies for establishing a biobank (including blood and urine samples) for any future retrospective studies. Creation of the biobank was approved by the Ethics Committee of Jinling Hospital (2017NZKY-013-01). This study was approved by the Ethics Committee of Jinling Hospital (2019NZKYKS-004-01) and was conducted in compliance with the Declaration of Helsinki. Demographic information, clinical data at the time of biopsy, and treatment and follow-up information were collected from patient medical records. A standard definition of multiple myeloma was applied.7 Clinical manifestations were defined as described previously.6 In our study of LCDD, we defined hematologic complete response as normalization of serum free light chain 1
Original Investigation (FLC) ratio, hematologic partial response as >50% decrease in FLCs from baseline, and hematologic nonresponse as ≤50% decrease in FLCs from baseline.6 As was done in a previous case series,8 hematologic complete response for heavy chain was defined by the disappearance of the circulating truncated monoclonal heavy chain by serum immunofixation. Improvement in kidney function was defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 or (2) ≥50% decrease (by at least 0.5 g) in 24-hour urine protein excretion in the absence of a reduction in estimated glomerular filtration rate ≥ 25% or an increase in serum creatinine level ≥ 0.5 mg/dL.6,9 Pathology Studies All kidney biopsies were processed using the standard light microscopy, immunofluorescence, and electron microscopy techniques.6,10 Tubular atrophy and interstitial fibrosis were scored semiquantitatively based on the percentage of the tubulointerstitial compartment affected and recorded as 0%, 1% to 25% (mild), 26% to 50% (moderate), or >50% (marked). Immunofluorescence was performed on cryosections (4 μm) using fluorescein isothiocyanate–conjugated polyclonal antibodies to IgG (IgG1-4), IgM, IgA, C3, C1q, and κ and λ light chains (Dako Corp). Ultrastructural evaluation was performed using a Hitachi 7500 transmission electron microscope. Statistical Methods Analysis was performed using SPSS, version 25.0, statistical software package (SPSS Inc). Two-sided P < 0.05 was considered statistically significant. Data are expressed as mean ± standard deviation or median with interquartile range for continuous variables and number with percentage for categorical variables. Survival analysis was performed by univariate survival analysis and Kaplan-Meier curves.
Results Demographics and Clinical Characteristics We retrospectively identified 25 patients with HCDD who had undergone kidney biopsy in the past 10 years, corresponding to 0.05% of biopsies. We also diagnosed 71 cases of LCDD (0.143%) and 8 cases of light and heavy chain deposition disease (0.016%). As shown in Table 1, of the patients with HCDD, 11 (44%) were women. Average age was 50.3 ± 9.6 years at the time of kidney biopsy. Median time from initial presentation to the time of biopsy was 8.0 months. Median serum creatinine level was 1.6 mg/dL and 68% of patients had serum creatinine levels > 1.2 mg/dL. Baseline average estimated glomerular filtration rate was 50.4 ± 28.0 mL/min/1.73 m2. Other presenting symptoms included hypertension (76%), peripheral edema (96%), nephrotic-range proteinuria (56%), microscopic hematuria (80%), and nephrotic syndrome (40%). None had macroscopic hematuria or extrarenal manifestations. 2
Table 1. Demographic and Clinical Characteristics of 25 Chinese Patients With HCDD at the Time of Kidney Biopsy Parameter Female sex Age at biopsy, y Time from initial presentation to kidney biopsy, mo Hypertension Edema Serum creatinine, mg/dL Serum creatinine > 1.2 mg/dL eGFR, mL/min/1.73 m2 Serum albumin, g/L Hypoalbuminemia (serum albumin < 35 g/L) Urine protein, g/24 h Nephrotic-range proteinuria, ≥3.5 g/24 h Microscopic hematuria Macroscopic hematuria Nephrotic syndrome Extrarenal manifestations Dialysis at biopsy
Value 11 (44%) 50.3 ± 9.6 8.0 (1-60) 19 (76%) 24 (96%) 1.6 (0.9-6.5) 17 (68%) 50.4 ± 28.0 29.6 ± 5.8 21 (84%) 4.0 ± 2.5 14 (56%) 20 (80%) 0 (0%) 10 (40%) 0 (0%) 0 (0%)
Note: Values for continuous data given as mean ± standard deviation or median (range); for categorical data, as count (percentage). Abbreviations: eGFR, estimated glomerular filtration rate; HCDD, heavy chain deposition disease.
Hematologic Characteristics Average hemoglobin level was 9.8 ± 2.0 g/dL, with anemia present in 84% of patients. Serum immunofixation electrophoresis was performed in 21 patients. Of the 10 (48%) patients who had detectable monoclonal protein, most (n = 8) had IgG λ light chain. Elevated FLC ratio (κ:λ > 1.65) was observed in 12 of 25 (48%) patients, and 3 of 25 (12%) had an FLC ratio < 0.26. Interestingly, at baseline, 2 of 25 (8%), 7 of 25 (28%), and 10 of 25 (40%) had κ FLC level, λ FLC level, and FLC ratio in the reference range, respectively. At the end of follow-up, the corresponding proportions were 2 of 13 (15%), 5 of 13 (38%), and 7 of 13 (54%) (Table S1). In total, 17 of 25 (68%) and 6 of 25 (24%) patients had hypocomplementemia of C3 and C4, respectively. Twentytwo patients underwent bone marrow biopsy. One patient had multiple myeloma diagnosed, with 13.5% plasma cells in bone marrow, serum monoclonal IgG λ light chain by serum immunofixation electrophoresis, and hemoglobin level of 9.1 g/L. Urine Bence-Jones protein test was negative in all 13 patients in whom it was performed (Table 2). Pathologic Characteristics Light Microscopy All cases were characterized by nodular mesangial sclerosis (Fig 1A and B). There was an average of 25.6 ± 7.6 glomeruli per biopsy specimen. Global sclerosis was found in 14 (56%) cases, with the percentage of globally sclerotic glomeruli ranging from 3% to 48%. Segmental sclerosis was noted in only 2 cases (affecting 3% and 10% of glomeruli). Fibrocellular crescents were present in 6 AJKD Vol XX | Iss XX | Month 2019
Original Investigation Table 2. Hematologic Characteristics at the Time of Kidney Biopsy Parameter Hemoglobin, g/dLa Anemia Monoclonal protein by sIFE IgG κ light chain IgA κ light chain IgG λ light chain Abnormal FLC ratio (<0.26 or >1.65) FLC ratio < 0.26 FLC ratio > 1.65 Median FLC concentration κ, mg/L λ, mg/L Hypocomplementemia C3 < 0.8 g/L C4 < 0.1 g/L Diagnosis of multiple myeloma ≥10% plasma cells on bone marrow biopsy
Value 9.8 ± 2.0 21/25 (84%) 10/21 (48%) 1 1 8 15/25 (60%) 3 12 66 52 17/25 (68%) 6/25 (24%) 1/25 (4%) 21/22 (95%)
Abbreviations: FLC, free light chain; IgG, immunoglobulin G; sIFE, serum immunofixation electrophoresis. a Mean ± standard deviation.
(24%) patients, with the percentage of fibrocellular crescents per biopsy ranging from 4% to 20%. Mesangial nodules were generally periodic acid–Schiff–positive and poorly argyrophilic (Fig 1A and C). Ten (40%) patients showed numerous fuchsinophilic deposits in the mesangial and subendothelial areas. Partial mesangiolysis was also observed in 5 cases (Fig 1B). However, there was no diffuse thickening of GBMs. Tubular atrophy and interstitial fibrosis were present in 22 (88%) patients and were marked in 5 (20%), moderate in 7 (28%), and mild in 10 (40%). TBMs were thickened and tortuous. Vascular lesions were observed in 23 (92%) cases, which were characterized by hyaline degeneration in arterioles and intimal thickening in interlobular arteries (Table 3). Immunofluorescence
All cases demonstrated linear deposits of monoclonal IgG along GBMs and TBMs (Fig 1D), but were negative for IgA, IgM, and κ and λ light chains. IgG subclass staining showed monotypic g heavy chains in all patients (g1, 13; g2, 2; g3, 6; g4, 2; g1 and g4, 1; and g2 and g4, 1). Seventeen patients had complement C3 and C1q deposits of the same pattern and intensity as IgG deposits. Two cases had C3 only, and 3 cases had no complement staining. Monotypic heavy chain staining was present in GBMs in all 25 cases, including the mesangium in 15 (60%), and also along TBMs in 76% of cases. Staining was also observed in Bowman capsule in 7 (28%) and arterial walls in 8 (32%) cases (Table 3). Electron Microscopy
Continuous (70%) or intermittent (30%) deposition of fine granular electron-dense material along the inner AJKD Vol XX | Iss XX | Month 2019
aspect of GBMs and outer aspect of TBMs was observed (Fig 1E and F). Deposits were also seen in the expanded mesangium in 64% of patients (Table 3). There was no organized substructure identified in deposits in any case. Eight (32%) patients showed injury to endothelial cells, presenting as widening of the subendothelial area, fibrin deposition, and exfoliation of endothelial cells. Endocapillary hypercellularity with neutrophil infiltration was present in 2 (10%) cases. In some areas, tubular cells were exfoliated from the TBMs, leaving the TBMs denuded. One patient had electron-dense deposits in a peritubular capillary wall. Extensive foot-process fusion (>50%) was observed in 9 of 22 patients (41%). Hypocomplementemia and g Isotypes Hypocomplementemia of C3 was more prevalent in g3HCDD (6 of 6 [100%]), followed by g1-HCDD (10 of 13 [77%]) and g2-HCDD (1 of 2 [50%]). Moreover, the patient with g1 and g4 HCDD also presented with a low C3 level. Neither of the 2 patients with g4-HCDD was found to have a reduced C3 level. A low C4 level was found only in g1-HCDD and g3-HCDD. Treatment and Outcomes Clinical follow-up was available for 20 of 25 (80%) patients. Average follow-up time was 40.1 ± 29.2 months after biopsy. Chemotherapy included thalidomide and dexamethasone (TD) in 8 patients; vincristine, Adriamycin, and dexamethasone (VAD) in 1; BD (bortezomib and dexamethasone) + TD in 2, VAD + BD in 1, and BD + TD + cyclophosphamide in 1. No one received an autologous stem cell transplant after chemotherapy. At last follow-up, in terms of light chain hematologic response, 4 of 10 (40%) patients were in complete response, 2 of 10 (20%) were in partial response, and 4 of 10 (40%) were in nonresponse. For heavy chain hematologic response, 1 of 20 (5%) was in complete response. For kidney function, 13 of 20 (65%) experienced an improvement and only 2 of 20 (10%) experienced a worsening (Tables 4 and S1). Seven patients (7 of 20 [35%]) did not receive chemotherapy before or after kidney biopsy, and 5 (71%) of these progressed to kidney failure, including 1 patient who died. Thirteen patients were treated with some form of chemotherapy; none progressed to kidney failure. Moreover, a higher percentage of patients in the chemotherapy group had kidney function improvement than that of the no-chemotherapy group (P = 0.001). For kidney failure, a lower percentage of patients in the chemotherapy group reached this end point than that of the nochemotherapy group (P = 0.001; Table 5). Number of globally sclerotic glomeruli was associated with risk for kidney failure on univariate analysis (P = 0.04; hazard ratio, 1.364; 95% confidence interval, 1.010-1.469). Other clinical and histopathologic parameters did not correlate with kidney survival. 3
Original Investigation
Figure 1. Heavy chain disposition disease with typical nodular glomerulosclerosis and ultrastructural features. (A) Increased mesangial matrix in the glomerulus, nodule formation (periodic acid–Schiff [PAS]; original magnification, ×200). (B) Partial mesangial dissolution (PAS; original magnification, ×400). (C) Nodules were poorly argyrophilic and containing capillary microaneurysms (periodic acid-silver metheramine; original magnification, ×200). (D) Immunofluorescence identified linear deposits of immunoglobulin G along the glomerular (GBMs) and tubular basement membranes (TBMs) (original magnification, ×200). (E, F) Finely granular or “powdery” electron-dense deposits were detected along the (E) inner aspect of GBMs (electron microscopy; original magnification, ×10,000) and (F) outer aspect of the TBMs (electron microscopy; original magnification, ×23,000).
According to the Kaplan-Meier survival analysis, kidney survival was remarkably poorer in the group with no chemotherapy (log-rank test P = 0.003, Gehan-BreslowWilcoxon test P = 0.005), but there were no significant differences among the different regimens of chemotherapy. Mean kidney survival of the chemotherapy group was 36.0 months, double the value of the nochemotherapy group (19.0 months; Fig 2).
4
Discussion In this study, we analyzed clinicopathologic features and outcomes of 25 patients with HCDD. To our knowledge, this is the largest experience of HCDD in the Chinese population; all prior series predominantly involved white patients.8,11,12 In our case series, clinical manifestations were similar to those in prior studies.8,12,13 However, we observed an AJKD Vol XX | Iss XX | Month 2019
Original Investigation Table 3. Pathologic Characteristics Parameter Light microscopy No. of glomeruli per biopsya Biopsies with globally sclerotic glomeruli Biopsies with segmental sclerosis Biopsies with fibrocellular crescent Biopsies with nodular mesangial sclerosis Biopsies with tubular atrophy and interstitial fibrosis Mild Moderate Marked Biopsies with vascular lesions Immunofluorescence Heavy chain g1 g2 g3 g4 g1 and g4 g2 and g4 Deposition of C3 Deposition of C1q Monoclonal deposits TBMs GBMs Mesangium Bowman capsule Vascular wall Electron microscopy TBM deposits GBM deposits Mesangium deposits Extensive foot-process fusion (>50%)
Value 25.6 ± 7.6 14/25 (56%) 2/25 (8%) 6/25 (24%) 25/25 (100%) 22/25 (88%) 10/25 (40%) 7/25 (28%) 5/25 (20%) 23/25 (92%)
13 2 6 2 1 1 19/25 (76%) 17/25 (68%) 19/25 (76%) 25/25 (100%) 15/25 (60%) 7/25 (28%) 8/25 (32%) 25/25 (100%) 22/22 (100%)b 14/22 (64%)b 9/22 (41%)b
Abbreviations: GBM, glomerular basement membrane; TBM, tubular basement membrane. a Mean ± standard deviation. b Specimens from 3 patients had no glomeruli observable with electron microscopy.
incidence (0.05%) lower than that reported by others.12 Compared with the study of Bridoux et al,8 patients in our study were younger, had less severely decreased kidney function, and had less frequently received chemotherapy. Our cohort had only g heavy chain deposition, while in study of Bridoux et al,8 2 classes of heavy chains (g, 15; α, 3) were found. These differences suggest that age of onset and severity level may be lower in Chinese versus white populations. In our series, no one had a diagnosis of extrarenal disease, compared with Bridoux et al,8 who reported that 3 patients had systemic manifestations, including liver cholestasis, nodular goiter, interstitial pneumonia, purpuric skin lesions, and ulcerative hemorrhagic esophagitis. In 2012, the International Kidney and Monoclonal Gammopathy Research Group recognized HCDD as a monoclonal gammopathy of renal significance–associated lesion.14 The monoclonal protein is due to an underlying AJKD Vol XX | Iss XX | Month 2019
plasma cell dyscrasia. Besides renal lesions, hematologic manifestations in our patients with HCDD were also remarkable. Anemia was present in 84% of our patients, but only 1 individual had severe anemia. Anemia may not always correlate with kidney function15 because it was also observed in individuals without apparent reduction in kidney function. In addition, the percentage of patients with a positive result on serum immunofixation electrophoresis was significantly lower in our study (48%) than that reported by Bridoux et al8 (80%). Three types of monoclonal immunoglobulin (ie, IgG κ, IgA κ, and IgG λ light chains) were noted in our study on serum immunofixation electrophoresis. In the Bridoux et al8 case series, the authors also observed IgA λ light chain. Moreover, only g-HCDD cases were observed in our cohort, while others have reported α-HCDD, μ-HCDD, and δ-HCDD in white patients. The type of FLC is often consistent with the type of serum abnormal monoclonal band. Ten of 15 patients with abnormal FLC ratios had monoclonal protein. The abnormal FLC ratio of the 10 patients is consistent with the monoclonal protein. Patients without monoclonal protein had abnormal FLC ratios manifested as excess κ light chain. Interestingly, 1 patient showed tissue deposition of IgG3, but serum immunofixation electrophoresis revealed monoclonal IgA κ light chain. It is unclear why only g heavy chains were seen in our cohort. A multicenter study is needed to collect more cases to answer this question in China. IgA monoclonal gammopathy does not appear to be less common in China versus other countries.16,17 The possibility of misdiagnosis is relatively small because electron microscopy is performed in every native biopsy case in our center. Using biopsies from the same period, we diagnosed light and heavy chain deposition disease in 8 patients (IgAλ, 2; IgG1λ, 1; IgG2λ, 1; IgG2κ, 1; IgG1κ, 2; and IgG3κ, 1). In our study, 2 patients had concurrent deposition of 2 types of IgG (IgG1 and IgG4, and IgG2 and IgG4, respectively; 1 of these 2 patients was previously reported by Yin et al18). The reason for the concomitant deposition of 2 subclasses of IgG is unclear. We observed that even when FLC concentration is within the reference range, the ratio may be abnormal. Likewise, even when FLC concentration is out of the reference range, the ratio may still be normal (Table S1). Nasr et al12 reported that among 4 patients with HCDD who underwent FLC testing, all had abnormal FLC ratios. The reason for this finding may be that the abnormal heavy chain causes the light chain to fail to assemble with it, resulting in an excess of the light chain, or it may be related to different types of light chain due to different sites of gene mutation19 that cannot be assembled with the normal heavy chain. However, because free heavy chains have a high affinity for tissues and are not concentrated in the circulation,20 immunofixation electrophoresis or assaying FLC ratio cannot be the confirmatory test. 5
Original Investigation Table 4. Treatment, Response, and Kidney Outcomes Hematologic Response Pt 1 2 3 5 8 9 10 11 12 13 14 15 16 17 18 19 22 23 24 25
Chemotherapy None TD TD TD None TD BD + TD + BD TD None TD TD BD + TD TD None None BD + TD + CTX VAD + BD VAD None None
Therapy Cycles
Light Chain CR
Heavy Chain
2 7 6 2+1+1 4 22 17 1 + 24 29
Always normal Always normal PR NR CR CR NR CR
2 + 19 + 6 4+2 4
PR NR NR
CR
Always normal
Kidney Function Outcomea Kidney failure Worsening Improved Improved Kidney failure Improved Improved Improved Kidney failure Improved Improved Improved Improved Improved Kidney failure Improved Improved Improved Kidney failure Worsening
Death No No No No Yes No No No No No No No No No No No No No No No
Note: Patients 4, 6, 7, 20, and 21 had no follow-up. Abbreviations: BD, bortezomib and dexamethasone; CR, complete response; CTX, cyclophosphamide; eGFR, estimated glomerular filtration rate; NA, not available; NR, no response; PR, partial response; Scr, serum creatinine; TD, thalidomide and dexamethasone; VAD, vincristine, Adriamycin, and dexamethasone. a Improved kidney function defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with eGFR ≥ 60 mL/min/1.73 m2 or (2) a ≥50% decrease (at least 0.5 g/ 24 h) in 24-hour urine protein excretion in the absence of a reduction in eGFR ≥ 25% or an increase in Scr level ≥ 0.5 mg/dL. Worsening kidney function was defined as >50% increase in Scr level from baseline but <6.0 mg/dl; kidney failure was defined as Scr level > 6.0 mg/dL or being dependent on kidney replacement therapy.
Among patients with hypocomplementemia, all had codeposition of complement components C3 and C1q, with most heavy chains being of IgG1 (9 of 17) and IgG3 (6 of 17) subclass, and the others being of the IgG2 (1 of 17) or IgG1 and IgG4 (1 of 17) subclass. These findings suggest that these heavy chains are sufficient to act on the classical pathway locally and systemically. Among patients with normal complement levels, 3 (all IgG1) had codeposition of C3 and C1q, suggesting that only the local complement classical pathway was active. One possible explanation is that structural differences in heavy chain subtypes may elicit different complement activation pathways. Two IgG4 cases had C3 only without C1q deposition, suggesting that perhaps the lectin pathway and/or alternative pathway were involved. Also, 3 cases (IgG2 and IgG4, IgG2, and IgG1) had no C3 and C1q deposition. Whether local and/or systemic activation of the classical complement pathway relates to the pathogenesis of HCDD continues to be unclear.8 Normalization of complement levels has been reported to occur during treatment.21,22 Future studies are needed to determine whether serum complement levels could be used as a biomarker of treatment response. Most (95%) glomeruli exhibited diffuse nodular mesangial sclerosis, resulting in an increase in glomerular volume. In our previous LCDD report, glomerular nodules occurred in 80%, which was also significantly higher than that
6
reported by others in white patients.6 These observations suggest that HCDD and LCDD nodules in Chinese people may be more obvious. Comparing the renal pathologic Table 5. Clinical Outcome According to Chemotherapy Treatment Chemotherapy
Improved kidney functiona Worsening kidney functionb Progression to kidney failurec Patient deaths Kidney survival, mod Patient survival, mod
Total (n = 20) 13
Yes (n = 13) 12
No (n = 7) 1
P 0.001
2
1
1
0.9
5
0
5
0.001
1 31.5 (1-118) 32.0 (1-119)
0 36.0 (4-74) 27.0 (1-119)
1 19.0 (1-118) 36.0 (4-77)
0.4 0.3 0.6
Abbreviations: eGFR, estimated glomerular filtration rate; Scr, serum creatinine. a Defined as: (1) a reduction in proteinuria to protein excretion < 0.5 g/d with eGFR ≥ 60 mL/min/1.73 m2 or (2) a ≥50% decrease (at least 0.5 g/24 h) in 24hour urine protein excretion in the absence of a reduction in eGFR ≥ 25% or an increase in Scr level ≥ 0.5 mg/dL. b Worsening kidney function was defined as >50% increase in Scr level from baseline but <6.0 mg/dL. c Kidney failure defined as Scr level > 6.0 mg/dL or being dependent on kidney replacement therapy. d Values expressed as mean (range).
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Original Investigation Supplementary Material Supplementary File (PDF) Table S1: Serum immunofixation electrophoresis and FLC findings in patients with HCDD.
Article Information Authors’ Full Names and Academic Degrees: Yuan Zhang, MD, Xiaomei Li, MD, Dandan Liang, MD, Feng Xu, MD, Shaoshan Liang, PhD, Xiaodong Zhu, MD, Nanjun Zheng, BS, Xianghua Huang, PhD, Zhihong Liu, MD, and Caihong Zeng, PhD. Authors’ Affiliation: Jinling Hospital Department of Nephrology, Nanjing Medical University, Nanjing, PR, China. Address for Correspondence: Caihong Zeng, PhD, Jinling Hospital Department of Nephrology, Nanjing Medical University, Nanjing, Jiangsu 210002, China. E-mail: [email protected]
Figure 2. Kaplan-Meier renal survival analysis, comparing patients with chemotherapy or not.
features of HCDD identified in our study and in the study by Bridoux et al,8 no statistical differences were found. In tubular atrophy/interstitial fibrosis, mild lesions accounted for the majority of cases in our cohort, while in Bridoux et al,7 moderate lesions accounted for the majority. Studies of monoclonal immunoglobulin deposition disease have demonstrated that lower initial kidney function is a predictive factor for progression to kidney failure.23 However, in our study, initial serum creatinine level did not predict the outcome of the disease. It may be because HCDD was found at a very early stage and responded well to chemotherapy or because the number of cases was too small to show statistical differences. Early diagnosis and treatment with BD appear to be important to preserve kidney function.8 Patients who received chemotherapy had a better prognosis than those who did not (P < 0.05). Although different chemotherapy regimens were used, all treated patients also had improved kidney function, and no treated patient developed kidney failure or died during chemotherapy treatment. No patients underwent stem cell transplantation in our center, so we were unable to judge the effect. Historically, the renal prognosis for patients with HCDD has been poor: 36% to 50% require hemodialysis within 1 year and 10% die within a mean duration of 12 to 76 months.23 In our study, outcomes appeared to be better than prior reports of white patients. We found that the kidney failure incidence within 1 year was 12%, and 5% died during follow-up. However, in our study of LCDD, 15 (34%)6 patients had stable or improved kidney function, significantly lower than HCDD (65%). In a case series at a single center in China, we found that HCDD in our patients presented exclusively with deposition of heavy chains of IgG class. Most individuals treated with chemotherapy could achieve improved kidney function, and adequate treatment for HCDD should be considered, especially for those in an early stage of the disease.
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Authors’ Contributions: Research idea and study design: YZ, CZ; data acquisition: YZ, XL; data analysis and interpretation: YZ, CZ, DL, FX, SL; statistical analysis: YZ; supervision or mentorship: CZ, DL, FX, SL, XZ, NZ, XH, ZL. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. Support: This research was supported by National Key R&D Program of China (2016YFC0901202), which had a role in study design and data collection; and National Natural Science Foundation of China (No. 81570644), which had a role in analysis and reporting. Financial Disclosure: The authors declare that they have no other relevant financial interests. Acknowledgements: We are grateful to Prof Xin Jin (Joseph) Zhou for revising the manuscript. Peer Review: Received February 13, 2019. Evaluated by 2 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form August 4, 2019.
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