Cryoglobulinemia in a moroccan nephrology department

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Saudi J Kidney Dis Transpl 2019;30(3):663-669

© 2019 Saudi Center for Organ Transplantation

Original Article

Cryoglobulinemia in a Moroccan Nephrology Department

Mounia Azizi, Hicham Rafik, Yassir Zajjari, Dina Ibrahim Montasser, Driss El Kabbaj Department of Nephrology, Dialysis and Renal Transplantation, Mohammed V Military Hospital,

Faculty of Medicine, Mohammed V, Souissi University, Rabat, Morocco

ABSTRACT. Cryoglobulinemia is a rare cause of kidney disease that occurs in patients with various diseases. Renal involvement often occurs after appearance of various clinical manifestations dominated by purpura and neuropathy. The aim of this study is to describe clinical, biological, and pathological characteristics of cryoglobulinemic glomerulonephritis (GN), as well as treatment and outcome. This is a retrospective study including all patients with positive cryoglobulin test and biopsy-proven GN secondary to cryoglobulinemia. Fourteen patients with cryoglobulinemic GN were collected. Their mean age was 46.92 ± 15.82 years with male predominance (64.28%). Weight loss, fever (71.42%), and purpuric rash (57.14%) were the main extrarenal manifestations. Eight patients presented with nephrotic syndrome (NS), associated with renal impairment in three patients. Four patients had rapidly progressive GN and two patients had acute kidney injury. Renal biopsy, performed in all patients, revealed membranoproliferative GN with glomerular thrombi in all patients. Crescents and necrotizing vasculitis were present in four patients. Hepatitis C virus (HCV) infection was the most common etiology. Antivirals and steroids or other immunosuppressive agents were used in most of the patients. During follow-up, complete response was observed in three patients and partial response was observed in four patients. Five patients had no response with renal injury requiring hemodialysis. NS with hematuria and renal insufficiency were the main clinical manifestations of cryoglobulinemic GN.

In our study, HCV infection dominated the etiologies, although not well described earlier. A half of our patients had poor outcome even after antiviral and immunosuppressive therapy.

Correspondence to:

Dr. Mounia Azizi,

Department of Nephrology, Dialysis and Renal Transplantation, Mohammed V Military Hospital, Faculty of Medicine, Mohammed V-Souissi University, Rabat, Morocco.

E-mail: mouniaazizi88@gmail.com

Introduction

Cryoglobulinemia is defined as the presence of immunoglobulins in the blood, which precipitate at a temperature lower than 37°C and redissolve upon warming of the serum.

¹

Renal involvement in cryoglobulinemia is commonly estimated to be around 50%. It often occurs after appearance of various clin-

Saudi Journal

of Kidney Diseases

and Transplantation

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ical manifestations dominated by purpura and neuropathy.

²

Cryoglobulinemia is a rare cause of kidney disease among patients with viral hepatitis C.

After discovery of a cryoglobulinemia, an etiological investigation is necessary. Type I monoclonal cryoglobulinemia are associated most often to lymphoproliferative diseases.

Mixed (types II and III) cryoglobulinemias are more often secondary to hemopathies, auto- immune pathologies, infectious diseases, or neoplasias. When the etiological investigation remains negative, it is called essential cryo- globulinemia.

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The aim of this study is to describe clinical, biological, and pathological characteristics of cryoglobulinemic glomerulonephritis (GN), as well as treatment and outcome.

Patients and Methods Study population

This retrospective study was conducted from January 2007 to December 2015 including all patients with positive cryoglobulin test and biopsy-proven GN secondary to cryoglobu- linemia at the Department of Nephrology Dialysis and Renal Transplantation in Military Hospital, Rabat, Morocco. The study was approved by the Ethical Committee of the institution.

Data collection

Available medical files, biological results, and histological parameters of all patients were retrospectively reviewed. Clinical parameters included renal and extrarenal symptoms (purpura, fever, arthralgia, myalgia, abdominal pain, cutaneous ulcers, neuropathy, and weight loss). Biological results included urinalysis (proteinuria from a 24-h collection and hema- turia), serum creatinine, rheumatoid factor, and complement factors C3–C4.

Detection of cryoglobulins

Cryoglobulins were measured as follows:

venous blood was collected in a warm syringe, transferred into warmed tubes, and stored at 37°C until it clotted. After centrifugation at

37°C, serum was collected and stored at 4°C for one week. After isolation and washing, the cryoprecipitate was quantified. Components of the cryoprecipitate were characterized using immunofixation.

Definitions

We defined complete response as disappea- rance of all clinical manifestations of active disease, disappearance of serum cryoglobulin and normalization of renal function, and no proteinuria and hematuria. A partial remission was defined by reduction of proteinuria by more than 50% without aggravation of renal function. All other patients were classified as nonresponse.

Statistical Analysis

Data with continuous variables were presen- ted as mean ± standard deviation. Categorical variables were presented as effective and percentage. Statistical analysis was performed with Statistical Package for the Social Sciences (SPSS) version 10.0 (SPSS Inc., Chicago, IL, USA).

Results Clinical features

Fourteen cases of cryoglobulinemic GN were collected. Nine (64.28%) patients were male and five (35.71%) were female; their mean age was 46.92 ± 15.82 years.

Ten patients showed weight loss and fever.

Cutaneous lesions were present in eight patients: vascular purpura in seven patients and cutaneous necrosis in one patient. Arthralgia was reported in three patients, preferentially affecting ankles, knees, and wrists. Arthritis was objectified in only one patient. Neurolo- gical involvement was present in eight patients. A sensorimotor peripheral polyneuro- pathy was diagnosed in seven patients, and electromyography showed axonal neuropathy.

No nerve biopsies were performed. One

patient had cerebrovascular event resulting in

stroke. All patients presented with lower limb

edema and hypertension.

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Laboratory features

Eight patients presented with nephrotic syn- drome (NS), associated with renal impairment in three patients. Four patients had rapidly progressive GN and two patients had acute kidney injury (AKI). Mean serum creatinine level at diagnosis was 3.02 ± 0.93 mg/dL and mean proteinuria was 2.43 g/24 h. Microscopic hematuria was present in all patients. Serum complement levels (C3 and C4) were in normal ranges in four of the 14 patients. A decrease in complement C4 levels was observed in 10 patients, seven of whom also had a low C3 serum level. Tests for rheu- matoid factors were positive in all patients.

Type II cryoglobulinemia was present in nine patients, type I in three patients, and type III in two patients. Type II cryoglobulins were polyclonal IgG and monoclonal IgM kappa.

The three monoclonal cryoglobulinemias were IgM kappa and IgG lambda isotype in one and two patients, respectively. All characteristics of patients are shown in Table 1.

Histological features

Renal biopsy, performed in all patients, revealed membranoproliferative GN with glomerular thrombi in all patients. Crescents and necrotizing vasculitis were present in four patients (Figures 1 and 2).

Immunofluorescence studies demonstrated subendothelial and intracapillary glomerular deposits of IgG, IgM, C3, C1q, kappa, and lambda light chains. For type I cryoglobu- linemia, the deposits were made up of the monoclonal cryoglobulin.

Associated pathologies

Cryoglobulinemia was considered essential in one patient and secondary in 13 patients.

Infectious diseases were the most frequent pathologies in our series: hepatitis C virus (HCV) infection in six patients and hepatitis B virus infection in one patient. Three patients presented with systemic diseases: systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Type I cryoglobulinemia was associated with two patients with multiple myeloma and one patient with non-Hodgkin’s

B-cell lymphoma.

Therapy and outcomes

Seven patients were treated with antiviral therapy: entecavir in the patient affected by chronic hepatitis B infection and combination of pegylated interferon-α and ribavirin in six patients with chronic hepatitis C infection.

Eleven patients were given corticosteroids as first-line therapy along with intravenous pulses of cyclophosphamide in five patients and with rituximab in six patients. Two patients with multiple myeloma were treated with chemo- therapy alone. A patient with non-Hodgkin’s B-cell lymphoma has been received chemo- therapy and rituximab. No plasma exchange was given in all cases.

With a median of follow-up of 36 months (range: 6–48 months), complete response was observed in three patients and partial response was observed in four patients. Five patients had no response with renal failure requiring hemodialysis. Two patients died of stroke and septic shock. Treatments and outcomes are depicted in Table 1.

Discussion

Cryoglobulinemia is a rare disease and its prevalence is unknown. Age and sex ratio of patients with is variable in different reported series. In a multicenter study of the northern Mediterranean, median age was 53 years and sex ratio female/male was 2.2.

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In our study, patients are younger (median age was 46.92 ± 15.82 years) with male predominance (64.28%).

Many organs may be affected by cryo- globulinemic vasculitis. However, most cryo- globulinemias (>80%) are asymptomatic.

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General signs were reported in 36% of cases.

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In our series, 71.42 % of patients showed weight loss and fever. The most suggestive skin manifestations are cold-triggered ischemic symptoms located on the extremities including Raynaud’s phenomenon, purpura, and skin necrosis.

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Cutaneous involvement was observed in nearly half of our patients.

Arthralgia or arthritis can affect the joints

ankles and hands or even knees and elbows.

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Table 1. Clinical features, treatment, and outcome of the study patients.

Patient Age

(Years) Gender Extrarenal symptoms

Renal symptoms

Cryoglobulin

typing Etiology Treatment Outcome

1 47 Male

Articular Peripheral nerve Weight loss

NS Type II Essential Corticosteroid

Rituximab

Complete response

2 52 Male

Cutaneous Weight loss

NS Type II Hepatitis B

virus

Entecavir Corticosteroid

Partial response

3 41 Female

Peripheral nerve Fever

NS Renal failure

Type II Hepatitis C virus

Pegylated interferon-α Ribavirin Corticosteroid Rituximab

Complete response

4 61 Male

Cutaneous Peripheral nerve

Acute kidney injury

Pegylated interferon-α Ribavirin Corticosteroid Cyclophosphamide

Nonresponse

5 36 Female

Articular Peripheral nerve Weight loss

NS Type II Hepatitis C

virus

Pegylated interferon-α Ribavirin Corticosteroid Cyclophosphamide

Complete response

6 50 Male

Cutaneous Articular Weight loss

RPGN Type II Hepatitis C virus

Nonresponse

7 35 Male

Cutaneous Peripheral nerve Weight loss

Acute kidney injury

Partial response

8 45 Male

RPGN Type II Hepatitis C virus

Death

9 32 Male

Peripheral nerve Fever

RPGN Type II Systemic

sclerosis

Corticosteroid

cyclophosphamide Nonresponse

10 28 Female Cutaneous

Articular RPGN Type III SLE Corticosteroid

Cyclophosphamide Nonresponse

11 40 Female Cutaneous

Articular NS Renal injury

Type III Rheumatoid arthritis

Corticosteroid

Cyclophosphamide Nonresponse

12 65 Female Stroke

Fever

NS Renal injury

Type I Multiple

myeloma Chemotherapy Death

13 67 Male Peripheral

nerve NS Type I Multiple

myeloma Chemotherapy Partial response

14 58 Male

NS Type I

Non- Hodgkin B lymphoma

Chemotherapy Rituximab

Partial response NS: Nephrotic syndrome, RPGN: rapidly progressive glomerulonephritis, SLE: Systemic lupus erythematosus.

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They are bilateral, symmetrical, and intermit- tent. They are not destructive contrary to rheumatoid arthritis with which joint damage related to cryoglobulinemia may be initially confounded due to the presence of a rheuma- toid factor.

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By the way, tests for rheumatoid factors were positive in all patients. Severe

forms of cryoglobulinemic vasculitis that could be fatal are rare and defined by the presence of acute renal injury, gastrointestinal vasculitis, pulmonary hemorrhage, or central nervous system involvement.

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Type I cryoglobulins consist of a mono- clonal immunoglobulin (often IgM, some- times IgG, and rarely IgA). Type II cryo- globulins are a mixture of a monoclonal component (typically IgM) possessing anti- body activity toward polyclonal IgG. Type III cryoglobulins are a mixture of more than one polyclonal immunoglobulin, typically poly- clonal IgM and IgG.

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Type II cryoglobuli- nemia was the most common in our study.

Kidney involvement, which is a major prog- nostic factor, was reported in all of our patients compared to 25% and 40% in other studies.

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Renal lesions typically manifest as glomerular disease characterized by NS or NS with acute renal injury and hematuria, some- times rapidly progressive GN.

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In the current study, eight patients presented with NS, four patients had rapidly progressive GN, and two patients had AKI. Renal pathology shows membranoproliferative GN with glomerular thrombi made of the cryoglobulin.

¹²

Ultra- structural studies may be required, especially when an atypical pattern is observed and shows massive subendothelial electron-dense deposits and an organized microtubular sub- structure of cryoglobulin deposits.

¹³

Etiological orientation depends essentially on immunochemical analysis of cryoglobulin.

Thus, type I cryoglobulinemias are always associated with lymphoplasmacytic prolife- ration.

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In our series, it was associated with two cases of multiple myeloma and one case of non-Hodgkin’s B-cell lymphoma. Mixed cryoglobulinemia could be associated with lymphoplasmacytic proliferation, autoimmune diseases, or infections.

³

Invernizzi et al repor- ted the presence of cryoglobulinemia in 27%

of cases of Sjogren’s syndrome, 26% cases of systemic lupus erythematosus, and 12.5%

cases of systemic scleroderma.

¹⁵

In a group of 16 Tunisian patients with cryoglobulinemia, 1 1 patients had systemic diseases, among them nine cases of lupus.

¹⁶

In our series, systemic

Figure 1. Renal biopsy in light microscopy,

Masson’s trichrome staining, showing three glomeruli with mesangial and endocapillary proliferation and mesangial matrix expansion.

Figure 2. Renal biopsy in light microscopy, Masson’s trichrome staining, showing endocapillary proliferation and double contours of glomerular capillary wall.

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diseases (3 cases) were rarer than infections (7 cases). Cryoglobulinemia could be present in 60%–90% of patients with HCV infection.

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Six of our patients had chronic HCV infection.

One patient with hepatitis B virus infection- associated cryoglobulinemia was identified in our study. Etiological survey may remain negative in 11%–71% of cases.

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Cryoglobu- linemia was considered essential in one of our patients.

Treatment of patients with symptomatic cryo- globulinemia should be modulated according to the pathophysiological mechanism (hypervis- cosity versus vasculitis) and the severity of clinical involvement. Management should include treatment of the cause of cryoglobu- linemia (chemotherapy and antiviral therapy).

Conventional immunosuppressive therapy is often used (corticosteroids, cyclophosphamide, and azathioprine) in moderate-to-severe forms.

The use of biotherapy such as B-cell depletion by rituximab is probably the most promising therapeutic approach, as reported in several series.

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Several series have reported the efficacy of rituximab in HCV-related cryo- globulinemia.

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In our study, rituximab was associated with corticosteroids in six patients, four of whom had a complete or partial response. On the contrary, cyclophosphamide was effective in only one of five cases.

Plasma exchanges can extract cryoglobulin from circulation and thus interrupt the pathogenesis mediated by immune complexes.

They are useful in patients with hyper- viscosity syndrome and in life-threatening conditions. In CryoVas series, 14% of patients received one or more plasma exchanges.

¹⁸

No plasma exchange was given in our study.

Prognosis is strongly influenced by the exis- tence of renal injury at time of diagnosis. The five-year survival is 90% in the absence of kidney damage; it is reduced to 50% in case of renal injury.

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The causes of death are vas- cular accidents, heart failure, severe infections, hepatocellular insufficiency, and the occur- rence of a lymphoproliferative syndrome.

¹⁴

A half of our patients had poor results, even with antiviral and immunosuppressive therapy, especially in severe forms.

Conclusion

NS with hematuria and renal insufficiency were the main clinical manifestations of cryo- globulinemic GN. HCV infection dominated the etiologies. A half of our patients had a poor outcome after antiviral and immunosup- pressive therapy.

Conflict of Interest: None declared.

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