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*
Department of Medicine at Harlem Hospital Center, New York, New
York.
Department of Medicine at Columbia Presbyterian Medical Center, New York,
New York.
Department of Pathology, Columbia University College of Physicians and
Surgeons, New York, New York.
Correspondence to Dr. Jen-Tse Cheng, Department of Medicine, Harlem Hospital Center, 506 Lenox Avenue, Room 12-101 KP, New York, NY 10037. Phone: 212-939-1453; Fax: 212-939-1306; E-mail: jc31{at}columbia.edu
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A group of 105 Italian patients with essential mixed cryoglobulinemic glomerulonephritis reported by Tarantino et al. were chosen as historical controls (22). Within this group, 85% of the 34 patients tested for anti-HCV antibodies were positive. Although this cohort clearly differed from ours with respect to demographic features and prevalence of anti-HCV antibodies, this historical control group provides the most detailed data available regarding long-term renal outcome of HCV infection (22).
Statistical Analyses
The Statistical Package for the Social Sciences (SPSS 7.5 for Windows) was
used for statistical analyses. Group data were expressed as mean ± SD
for continuous variables with Gaussian distribution or as median and ranges
for variables with skewed distribution. For categorical variables, the results
were expressed as percentage or ratio. Differences in the group results
between this patient cohort and historical controls were evaluated by
t test or 
2 analysis. The actuarial survival was
calculated by the method of Kaplan and Meier
(23), and comparison between
survival curves was made by the log-rank test.
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Results |
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The reasons for renal referral were nephrotic syndrome or nephrotic
proteinuria with renal insufficiency in 10 patients (71%), chronic renal
insufficiency in two (14%), acute renal failure in one (7%) and uremia in one
(7%). Hypertension, defined as systolic BP (SBP) of 140 mmHg or greater or
diastolic BP (DBP) of 90 mmHg or greater was noted in eight patients (57%) and
included stage 1 in two patients (SBP 140 to 159 or DBP 90 to 99), stage 2 in
three patients (SBP 160 to 179 or DBP 100 to 109), and stage 3 in three
patients (SBP 
180 or DBP 110)
(24). Eight patients (57%) had
peripheral edema, which was massive in six (43%). No patient had palpable
purpura or arthritis.
Urinalysis with microscopic examination of the urine sediment showed 3 to 4+ proteinuria in 12 patients (86%) and microhematuria in 13 patients (93%) with red cell casts in three patients. The mean 24-h urine protein was 8.4 ± 8.2 g, and the mean creatinine clearance at the time of renal biopsy was 34.6 ± 17.1 ml/min.
The mean values of serum chemistries at the time of renal biopsy were: creatinine 3.5 ± 3.9 mg/dl, albumin 2.3 ± 0.8 g/dl, and cholesterol 150 ± 60 mg/dl. The liver enzymes were mildly elevated in 11 patients (79%): The mean serum aspartate aminotransferase was 74 ± 35 U/L (normal <40 U/L), and the mean alanine aminotransferase was 32 ± 19 U/L (normal < 36 U/L). Only one patient (patient 5) had clinically acute liver disease with jaundice. All patients were anemic with the mean hematocrit of 29.2 ± 3.9%. Hypocomplementemia was present in six of 13 patients (46%) and cryoglobulinemia was detected in four of 12 patients (33%). Rheumatoid factor was present in two of 9 patients (22%) tested.
Renal Pathology
The renal biopsy findings are summarized in
Table 2. The major pattern of
glomerular disease was MPGN, including six cases of MPGN type 1 and five cases
of MPGN type 3, of the Burkholder subtype. One patient with MPGN type 3 was
further subcategorized as an unusual example of immunotactoid glomerulopathy
(described in detail in reference
(25). The remaining three
patients had MGN with atypical features.
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Among the six patients with MPGN type 1, all displayed varying degrees of mesangial proliferation with peripheral mesangial interposition, duplication of glomerular basement membrane, and accentuated glomerular lobularity (Figure 1). In two of these cases, crescents were identified involving 5 and 17% of glomeruli, respectively. The major immune reactants detected by immunofluorescence were IgM (six patients), IgG (five patients), C3 (six patients), and C1 (four patients), with only sparse and weak staining for IgA (three patients). On ultrastructural evaluation (available in five patients), deposits were typically in combined mesangial and subendothelial locations. In three patients, occasional subepithelial deposits were also seen, but without sufficient number or regularity to qualify as MPGN type 3. No case of MPGN type 1 had organized deposits (with tubular or fibrillar substructure) at the ultrastructural level. One patient (patient 9) lacked any detectable electron-dense deposits by electron microscopy in spite of well-developed membranoproliferative features by light microscopy and 2+ glomerular staining for IgM, C3, and C1. This patient also had had a recent episode of microangiopathic hemolytic anemia with schistocytes identified in the peripheral blood smear, acute thrombocytopenia, and anemia. The combination of clinical and renal biopsy features suggested the possibility of a membranoproliferative pattern secondary to subacute thrombotic microangiopathy, although no actual fibrin thrombi were detected.
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MPGN type 3 of the Burkholder subtype, identified in five patients, presented a mixed pattern of membranoproliferative and membranous glomerulonephritis (Figure 2). The membranous component was visible by light microscopy as variably thickened and rigid glomerular basement membranes with spikes or internal vacuolizations, often superimposed on double-contoured basement membranes. Two of the five patients had crescents involving 19 and 41% of glomeruli, respectively. By immunofluorescence, four had codeposits of IgG and IgM and one had IgM as the only Ig deposited. All five patients demonstrated deposits of C3, and three also had positivity for C1. By electron microscopy, deposits were in combined mesangial, subendothelial, and subepithelial locations. The only specimen with organized deposit substructure was from patient 11 with immunotactoid glomerulopathy (25). In this patient, electron microscopy disclosed voluminous deposits of stacked tubular structures ranging from 35 to 45 nm in diameter in the subendothelial, subepithelial, and mesangial locations.
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Among the three patients with MGN, all displayed morphologic features atypical for idiopathic MGN. In one patient, there was focal segmental and global glomerulosclerosis with collapsing features and podocyte reactivity suggesting overlap with HIV-associated nephropathy (HIVAN). One patient had a segmental MGN with diffuse mesangial proliferative features and abundant mesangial deposits detected by electron microscopy. The third patient had MGN with focal segmental endocapillary proliferative and exudative glomerulonephritis characterized by many infiltrating neutrophils, but without mesangial interposition or duplication of the glomerular basement membranes. In all three patients, deposits were detected in the subepithelial and mesangial regions. A few subendothelial deposits were also identified in the patient with mesangial proliferative features. No patient had organized deposits. By immunofluorescence, deposits consisted of IgG alone in one patient, C3 alone in one patient, and combined deposits of IgG, IgM, IgA, C3, and C1 in the patient with membranous and exudative glomerulonephritis.
Post mortem examination in two patients (patients 1 and 7) showed micronodular cirrhosis of the liver and persistent MPGN with similar histologic features to those noted in the previous renal biopsies.
Clinical Course and Outcome
Follow-up was available in 13 patients (93%) and ranged from 1 wk to 46 mo
(mean 14 mo) after renal biopsy. Table
1 summarizes the time intervals from the diagnosis of HCV-GD to
the development of the specific end points of advanced renal failure,
initiation of dialysis, and death.
Advanced renal failure, defined by a doubling of baseline serum creatinine concentration and/or an increase in serum creatinine above 4 mg/dl, developed in 10 patients (71%). One of these patients (patient 14) was already on dialysis when a renal biopsy was obtained. Five patients (43%) progressed to dialysis within a median time of 2.4 mo (range, 1.8 to 22.4 mo). Among the six patients on dialysis, four died within a median time period of 5.0 mo on dialysis (range, 0.3 to 43.8 mo). The causes of death were uremia in one (patient 1 who refused further dialytic therapy), sepsis in two (patients 2 and 3), and metastatic adenocarcinoma of the lung in one (patient 6). The remaining two patients were on dialysis for 5.9 and 20.5 mo, respectively. Among the remaining four patients with advanced renal failure not requiring dialysis, two died of nonrenal causes (patient 7 of pneumonia and drug intoxication; patient 9 of end-stage AIDS), one showed continued worsening of renal function, and one with AIDS was lost to follow-up.
For the four patients with relatively stable renal function, two died within a period of 0.6 and 6.4 mo, respectively, after biopsy. The causes of death were pulmonary hypertension with right heart failure in one (patient 4) and unknown in the other (patient 12). The remaining two patients (patients 5 and 8) are alive with stable renal function at 28.5 mo and 28.6 mo, respectively, after renal biopsy.
A Kaplan-Meier survival curve for all 14 patients using dialysis or death as the end point is shown in Figure 3. Survival analysis of the historical controls (22) was superimposed on that of the present cohort for visual comparison. The median time to dialysis or death among the HIV-infected patients with HCV-GD was 5.8 mo (95% confidence interval, 1.3 to 10.3 mo). In comparison, Tarantino et al. reported a 49% 10-yr survival (free of death or chronic renal failure) in 105 patients with essential mixed cryoglobulinemic glomerulonephritis (22). Further stratification of the present cohort into AIDS versus non-AIDS groups revealed a higher mortality and a significantly shorter survival time for AIDS patients regardless of whether they received dialysis. Five of six AIDS patients (83%) were dead at the close of the study versus three of eight non-AIDS patients (38%). The median patient survival time was 6.1 mo for the AIDS group versus 45.9 mo for the non-AIDS group (log-rank test P = 0.02).
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-Interferon was administered to three patients. The regimen
consisted of 3 million units given subcutaneously 3 times per week for 6 mo.
One patient (patient 2) completed a full course of treatment. In one patient
(patient 3), treatment was discontinued after 5 mo because of the development
of advanced renal failure. In the third patient (patient 6), the treatment was
discontinued after 3 mo because of severe mental depression. No improvement in
renal function or survival time was noted in any of the three patients.
Angiotensin-converting enzyme (ACE) inhibitor was not used (except for patient
12) because of the high prevalence of moderately advanced renal insufficiency
and/or hyperkalemia. Glucocorticoids were only used for adjunct therapy of
pneumocystis carinii pneumonia with hypoxemia.
In summary, at the close of this study, eight patients (57%) were dead with median survival of 6.1 mo, five patients (36%) were alive, and one patient (7%) was lost to follow-up.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stokes et al. reported 12 HIV and HCV coinfected intravenous drug users, seven blacks and five Hispanics, who presented with proteinuria, microhematuria, and elevated serum creatinine (20). Edema, hypertension, and hypocomplementemia were noted in the majority of patients, and 42% of patients had cryoglobulinemia (20). Renal biopsy showed MPGN in five, mesangial proliferative glomerulonephritis in five, MGN in one, and collapsing glomerulopathy with immune complex deposits in one patient (20). Three patients died and five patients progressed to end-stage renal failure in the course of follow-up with a mean time to dialysis of 8.4 mo after biopsy (20). Our cohort differs from that of Stokes et al. with respect to the greater percentage of African-Americans (93%) and the lower prevalence of hypocomplementemia (46%) and cryoglobulinemia (33%) despite a higher prevalence of MPGN. Overall, morbidity and mortality were higher in our patients, with median combined renal/patient survival of only 5.8 mo. The majority of our patients died with renal failure, but the major causes of death were nonrenal and related to complications of long-term HIV infection. Although we observed a similar spectrum of glomerular lesions, our patients had a particularly high prevalence of MPGN type 3, a more complex glomerular lesion characterized by mesangial, subendothelial, and subepithelial deposits. Although cryoglobulinemia was detected in 33% of patients in this study, only one patient had organized deposits. These findings differ from the high rate of substructure identification in glomerular deposits of HCV-GD from non-HIV-infected patients (9,13).
In our patients with HCV and HIV coinfection, the HCV-GD became clinically evident in the setting of moderately to far-advanced HIV infection. Eighty-six percent of the patients had CD4+ T cells below 500/µl and 43% of patients had AIDS. The majority of patients presented with nephrotic syndrome or nephrotic proteinuria and renal insufficiency. These clinical presentations are similar to those reported for patients with HCV-associated MPGN (HCV-MPGN) without HIV coinfection (9,13). However, the degree of renal insufficiency in these HIV-infected patients with HCV-GD was more advanced than reported in patients with HCV-MPGN (9,13). The mean serum creatinine was significantly higher (3.5 mg/dl versus 1.8 mg/dl, P < 0.025), and the mean creatinine clearance was significantly lower (35 ml/min versus 51 ml/min, P < 0.05) in our HIV-infected patients with HCV-GD compared to reported patients with HCV-MPGN without HIV (9,13). Despite massive proteinuria with severe hypoalbuminemia and edema, hypercholesterolemia was typically absent, as described for HIV AN (26). Hypocomplementemia and/or cryoglobulinemia were present in less than half of the patients, a lower prevalence than reported in HCV-GD without HIV coinfection (9,13). Thus, the absence of hypocomplementemia, cryoglobulinemia, or rheumatoid factor cannot reliably exclude HCV-GD in HIV-infected patients.
Studies of the clinical course of cryoglobulinemic glomerulonephritis, a
form of MPGN induced by HCV, have described a predominantly chronic and
indolent course with variable episodes of acute exacerbations and remissions
(22,27,28).
Progression to end-stage renal failure requiring dialysis was unusual, and
chronic uremia developed in only 10% of the patients several years after the
onset of renal symptoms
(27,28).
The cumulative 10-yr survival without renal failure was 49%
(22). Among the subgroup with
initial serum creatinine > 1.5 mg/dl, the 30-mo renal survival was 60%
(22). A study on the effect of
-interferon therapy in patients with HCV-GD showed a significant
reduction in proteinuria and an improvement in serum creatinine of 0.2 mg/dl
or greater in 11 of 14 patients over 6 to 12 mo
(13). By contrast, 71% of our
HIV-infected patients with HCV-GD progressed rapidly to advanced renal
failure, and 50% of them required dialysis within a median interval of 2.3 mo
after biopsy. Although all of our patients had creatinine values greater than
1.5 mg/dl at diagnosis, outcome was far worse than for the subgroup of
historical controls with similar initial creatinine levels (21%
versus 60% 30-mo survival). Mortality was high (57%) with median
renal/patient survival of only 5.8 mo. -Interferon treatment in three
patients did not prevent the development of renal failure, nor did it prolong
patient survival. This pattern of rapid deterioration of renal function mimics
the clinical course of HIV AN
(26,29,30).
Although the presence of hypertension, microscopic hematuria with active urine
sediment, and hypocomplementemia may serve as clues to the possible presence
of glomerulonephritis, the distinction between HCV-GD and HIV AN can only be
made by renal biopsy.
The causes of this poor outcome and the resistance to -interferon
treatment remain speculative. Only one patient had overlapping features of
collapsing glomerulopathy and HCV-GD. Although crescents were identified in
four cases, these involved a minority of glomeruli. The large percentage of
glomeruli with complex glomerular lesions, particularly MPGN type 3, may have
influenced the poor renal survival. Sepsis as the leading cause of death
suggests that double viral load and a possible increase in HIV viral RNA in
advanced renal failure (31)
contributed to higher mortality. Progressive glomerulosclerosis also may have
been promoted by both HIV coinfection and risk factors related to black race.
Racial factors, whether biologic or socioeconomic, have been shown to
adversely affect the outcome of other glomerular diseases such as lupus
nephritis, HIV AN, and idiopathic collapsing focal glomerulosclerosis
(29,32,33,34,35),
and may explain some of the observed differences in renal/patient survival in
HCV-GD compared to historical controls. In summary, it is likely that the
combined influences of complex glomerular lesions, higher baseline renal
insufficiency, double viral burden, and black race promote rapid renal
deterioration and high mortality in HIV-infected patients with HCV-GD.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-interferon therapy. Kidney Int46
: 1700-1704,1994[Medline]
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