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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 3  |  Page : 572-579
Herb-induced acute bone marrow intoxication and interstitial nephritis superimposing glomerular C1q deposition in a patient with paroxysmal nocturnal hemoglobinuria

1 Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City and College of Medicine, King Saud University for Health Sciences, Riyadh, Saudi Arabia
2 Department of Pathology, King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia

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Date of Web Publication20-May-2015


Paroxysmal nocturnal hemoglobinuria is a rare disease of the red blood cell membrane that renders it lyzable by the complement system, leading to chronic intravascular hemolysis. Renal hemosiderosis is a well-known complication of intravascular hemolytic anemia and can lead to acute kidney injury and renal failure. The use of herbal medicine is common worldwide. The nephrotoxicity of herbal remedies can take several forms, which include acute kidney injury and acute and chronic interstitial nephritis. In addition, the use of herbal remedies can result in bone marrow toxicity and suppression. C1q nephropathy is an uncommon form of glomerular disease characterized by dominant or co-dominant glomerular immunofluorescence positivity for C1q in the absence of clinical and serological evidence of systemic lupus erythematosus, and has various clinical presentations and outcome. Here, we report a patient of undiagnosed paroxysmal nocturnal hemoglobinuria who consumed herbal medicine of unknown constituents and clinically presented with anemia and acute kidney injury. The pathological findings of bone marrow and renal biopsies that include bone marrow intoxication, severe renal hemosiderosis and acute interstitial nephritis and kidney injury, as well as co-dominant glomerular deposition of C1q, are discussed. In addition, we discuss and hypothesize the possible pathogenesis of glomerular C1q deposition in the setting of paroxysmal nocturnal hemoglobulinuria.

How to cite this article:
Boqari DT, Al Faraj S, Arafah M, Aloudah N, Alkhairy KS, Alsuhaibani A, Alsaad KO. Herb-induced acute bone marrow intoxication and interstitial nephritis superimposing glomerular C1q deposition in a patient with paroxysmal nocturnal hemoglobinuria. Saudi J Kidney Dis Transpl 2015;26:572-9

How to cite this URL:
Boqari DT, Al Faraj S, Arafah M, Aloudah N, Alkhairy KS, Alsuhaibani A, Alsaad KO. Herb-induced acute bone marrow intoxication and interstitial nephritis superimposing glomerular C1q deposition in a patient with paroxysmal nocturnal hemoglobinuria. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Jun 14];26:572-9. Available from: https://www.sjkdt.org/text.asp?2015/26/3/572/157384

   Introduction Top

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic stem cell (HSC) disorder that leads to chronic intravascular hemolysis, episodes of venous thrombosis and bone marrow suppression. PNH results from HSC that acquires a somatic mutation in an X-linked, phosphatidylinositolglycan anchor biosynthesis class A (PIG-A) gene. The product of this gene is necessary for the first step in the biosynthesis of glycosylphosphatidylinositol (GPI), a glycolipid moiety that tethers GPI-anchored complement regulatory proteins CD55 and CD59 to the plasma membranes. Mutation in the PIG-A gene leads to reduction or absence of CD55 and CD59 expression from the red blood cells (RBC) membrane and renders RBC vulnerable to complement-mediated hemolysis. [1],[2] Clinical polymorphism of PNH has been recognized by two presentations: One form, predominantly hemolytic without overt bone marrow failure (classical PNH) and the other one, with bone marrow suppression and failure (aplastic anemia-PNH syndrome). [3] Chronic repetitive episodes of intravascular hemolysis in PNH leads to release of free hemoglobin, which contributes to the clinical manifestations of PNH, including fatigue, esophageal spasm, erectile dysfunction and thrombosis. Renal tubular epithelial cell hemosiderosis can be secondary to conditions associated with intra-vascular hemolysis, such as PNH, valvular heart disease and prosthetic heart valve implants. [4] Intracellular accumulation of iron causes injury to cellular organelles and results in acute and chronic tubular injury. [5],[6]

Herbal medicines are popular in some regions of the world and among certain sections of society. The use of biochemically different herbs as an alternative therapy has increased universally. Toxicity can occur when herbal remedies with unknown toxicity are consumed, the substitution of an innocuous herb with a toxic one, preparations are contaminated with toxic non-herbal compounds or when pharmacologically the herb potentiates a toxic effect of a conventional therapy. [7] Various patterns of kidney injury were reported after the use of herbal medicines, including acute kidney injury/acute tubular necrosis, acute and chronic interstitial nephritis, Fanconi's syndrome, renal papillary necrosis, systemic lupus erythematosus-like syndrome, [8] nephrolithiasis and malignancy. [9] Herb preparations can also have a potent inhibitory effect on the clonogenic response of human bone marrow cells, which can result in leukopenia, thrombocytopenia and aplastic anemia. [10] In addition, herbal medicines can be associated with autoimmune intravascular hemolytic anemia. [11]

C1q nephropathy is an uncommon, distinct entity, characterized by the presence of glomerular dominant or co-dominant deposition of C1q component of the complement system, corresponding ultrastructural glomerular immune-type dense deposits and absence of clinical and laboratory evidence of systemic lupus erythematosus (SLE). C1q nephropathy has a variable clinical presentation that includes increase in serum creatinine, hematuria, nephrotic range proteinuria and the nephrotic syndrome and hypertension. [12] Similar to its clinical presentation, the histological manifestations and clinical outcome of C1q nephropathy vary considerably.

Herein, we report a patient of undiagnosed PNH who presented clinically with anemia and acute kidney injury, discuss the histopathological findings of the bone marrow and renal biopsies and explore the possible relationship between C1q mesangial deposition and PNH.

   Case Report Top

A 48-year-old woman presented with a history of loss of appetite, lethargy and vomiting for approximately 10 days. The patient's use of a local herb-based formula of unknown biochemical constituents for two weeks was discovered by medical inquiry. Her medical history was significant for iron deficiency anemia of unknown cause, which required, in another institution, one time blood transfusion and a short course of oral iron supplement two years before presentation. There was no history of previous or ongoing acute infectious disease.

At the time of admission, she was conscious and her temperature was 38.4°C. The rest of her vital signs were within normal limits. Her physical examination was unremarkable and there was no evidence of rash, jaundice, lower limb edema or arthalgias. Urinalysis showed 39 and 28 RBC and WBC per HPF, respectively, and was negative for glucose, bilirubin, ketones and hemoglobinuria. Liver function tests were within normal limits. Her renal profile showed blood urea nitrogen (BUN): 42.5 mmol/L, serum creatinine: 792 μmol/L and serum albumin: 39 g/L. Her serum sodium and potassium levels were 130 and 5.3 mmol/L, respectively. A 24 h collection of urine showed protein content of 0.95 g. Complete blood count revealed pancytopenia with WBC 2.6 × 10 9 /L (differential showed lymphocytes 50%, neutrophils 22% and eosinophils 4%), RBC 2.45 × 10 12 /L and platelet 119 × 10 9 /L. Her hemoglobin was 67 g/L, Hct: 0.229 L/L, MCV: 93.7 mm/L, MCH: 33.1 pg and MCHC: 353 g/L. The erythrocyte sedimentation rate was 140 mm/HR. Her reticulocyte count was 0.80%, with an absolute reticulocyte count of 17.8 × 10 9 /L (reticulocytosis ranging from 10 to 15%). Blood smears confirmed the patient's leukocytopenia and thrombocytopenia, but showed no schistocytes. The patient's iron level was 10.5 μmol/L and ferritin level was 2291 μg/L. Coombs test was negative. There was no hypocomplementemia. Although search for hemosiderinuria was overlooked, the patient had hypohaptoglobulinemia (<0.08 g/L; normal range 0.35-2.50) and an elevated serum LDH (407 μ/L; normal range 125-243). Serologically, ANA and anti-DNA were within normal limits, rheumatoid factor 19.9 IU/ ML and C-ANCA and P-ANCA were 14.86 and 16.02 units, respectively. Chest X-ray was unremarkable and abdominal ultrasound showed normal kidneys.

Renal biopsy was performed and two cores of renal tissue were obtained. Two-micrometer-thick sections from the formalin-fixed, paraffinembedded tissue were stained with hematoxylin and eosin, periodic acid Schiff, Masson's trichrome and methenamine silver special stains. For immunofluorescence, 3 μm cryostat sections were stained with fluorescein isothiocyanate (FITC)-conjugated rabbit antihuman IgG, IgM, IgA, C3, C4, C1q and kappa and lambda light chains (Dako, Carpinteria, CA, USA). The intensity of immunofluorescence positivity was graded on a scale of 0, trace; and 1 to 3+. Electron microscopy was performed on glutaraldehyde-fixed tissue with a JOEL1230 electron microscope (Akishima, Japan).

Light microscopic examination showed mild segmental increase in mesangial matrix without an increase in mesangial cellularity. The glomerular capillaries were patent and there was no evidence of segmental glomerular scarring [Figure 1]. No proliferative features such as endocapillary or extracapillary hypercellularity, subendothelial deposits, fibrinoid necrosis and karyorrhexis were identified. The interstitium showed mild edema and moderate inflammation, of which the inflammatory infiltrate consisted mainly of lymphocytes and plasma cells. Scattered neutrophils and eosinophils were also noted [Figure 2]. No granulomas were identified. Numerous golden refractive, variably sized intracytoplasmic granules were identified in the epithelial cells of the proximal and distal renal tubules, along with a moderate degree of acute tubular epithelial cell degenerative and regenerative changes [Figure 1]. Prussian blue special stain for iron demonstrated diffuse tubular epithelial cell hemosiderosis [Figure 1], inset). There was no interstitial fibrosis or tubular atrophy. The interstitial arteriolar and arterial blood vessels were unremarkable. Immunofluorescence microscopy demonstrated diffuse global co-dominant intense fine granular mesangial staining for C1q (3+) [Figure 3]A. A similar staining pattern for IgG (3+) was also observed [Figure 3]B, along with kappa (2+) and lambda (2+) light chains. There was no staining for IgM, IgA, C3 and C4. Ultra-structural examination showed variably sized glomerular immunetype-dense deposits confined to the mesangial and paramesangial areas [Figure 4]. Effacement of the foot processes of the visceral epithelial cells was noted over a short segment of the glomerular basement membranes. No tubuloreticular inclusions were identified.
Figure 1: Mild increase in mesangial matrix is noted in this glomerulus. Marked tubular epithelial cell hemosiderosis is seen (PAS ×200). Prussian blue special stains highlight the iron deposition of the tubular epithelial cells (inset ×200).

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Figure 2: Interstitial inflammatory cell infiltrate consisting of lymphocytes, plasma cells and scattered eosinophils (PAS ×200).

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Figure 3: Immunofluorescence microscopy shows co-dominant 3+ global fine granular mesangial staining for C1q (A) and IgG (B) (immunofluorescence micrograph ×200).

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Figure 4: Electron micrograph shows mesangial immune-type-dense deposits (transmission electron microscopy, urinyl acetate and lead citrate stain, ×20,000).

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Hematology consultation workup revealed a positive screening test for paroxysmal nocturnal hemoglobinuria in the form of flow cytometrically reduced expression of CD55 and CD59 on the RBCs (36% and 23%, respectively) [Figure 5]. Bone marrow biopsy showed morphological features compatible with toxic bone marrow damage in the form of interstitial edema, loss of hematopoietic cellular elements and multiloculation of the adipocytes [Figure 6].
Figure 5: Histogram exhibits red blood cells negative (red), partially positive and positive (blue) for CD59.

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Figure 6: Bone marrow biopsy shows interstitial edema, reduction in the hematopoietic cellular elements and multiloculation of the adipocytes, compatible with drug/herb-induced acute bone marrow intoxication (H&E ×400).

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The patient was started on oral prednisolone 30 mg/day and underwent three sessions of dialysis. Her creatinine gradually decreased, and, at the time of discharge and at the ninemonth follow-up, the creatinine level was 256 and 69 μmol/L, respectively. [Table 1] summarizes the clinicopathological findings.
Table 1: Clinical, laboratory and pathological findings.

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   Discussion Top

In PNH, the breakdown of RBC membranes by complement leads to the release of hemoglobin into the circulation and subsequent hemosiderosis. In the current case, the accumulation of a large amount of iron in the tubular epithelial cells could result in cellular damage and contributed to the development of clinical manifestations and pathological features of acute kidney injury. Reversible hemosiderosis-related acute kidney injury secondary to PNH has been reported. [13] Bone marrow failure is generally present in all patients with PNH, even when peripheral blood counts are normal. The morphological changes in the bone marrow in PNH are variable, and range from normocellular and hypercellular to severely trilinear depletion of hematopoietic cells and replacement of the cellular elements of the bone marrow by adipocytes, resulting in aplastic anemia. Morphological features of myelodysplastic bone marrow and myelofibrosis can coexist with the PNH. Histopathological examination of the bone marrow in the current case demonstrated depletion of the hematopoietic cellular elements along with significant edema and multiloculation of the bone marrow adipocytes. The latter two histological features are usually not seen in PNH, but are well established in another cause of bone marrow suppression; acute drugor herb-induced bone marrow toxicity.

Acute interstitial nephritis (AIN) is a known cause of acute kidney injury and failure and can be associated with macroscopic hematuria, fever and sometimes other allergic clinical manifestations. Nephrotoxic drugs and increasingly recognized herbal medicines lead to AIN. Histologically, renal biopsies reveal interstitial inflammatory cell infiltrate predominantly composed of focal lymphocytes, plasma cells and eosinophils. Acute tubular epithelial cell degenerative and regenerative changes and interstitial edema are found during the acute phase of the disease. [14] The main target of herbinduced AIN seems to be the renal tubular epithelial cells. [7] Progression to chronic interstitial nephritis can occur, and occasionally morphological features of chronicity such as hypocellular interstitial fibrosis and atrophy and loss of renal tubules develop rapidly. [15] In our patient, although the morphological findings in renal biopsy can be explained by the effect of massive renal hemosiderosis, the interstitial changes might reflect herbal-induced AIN, and clinical response to steroid treatment may be supportive to this conclusion. Information on the exact dose consumed, frequency of usage and constituents of the ingested herb were not available.

The presence of co-dominant immunofluorescence positivity for C1q and corresponding ultrastructural immune-type-dense deposits is an interesting pathological finding, which, to the best of our knowledge, has not been previously reported in a similar clinical setting. C1, the first component of the complement system, is a large multimeric protein complex composed of five molecules: A single C1q, two C1r and two C1s. The complement cascade begins when the CH2 domain of immunoglobulin G (IgG) binds to C1q, leading to activation of C1r and C1s and initiation of a cascade of downstream events. Generally, C1q glomerular deposition is caused by the activation of C1q by IgG and IgM; therefore, C1q nephropathy is considered as an immune complex glomerulonephritis. However, it remains unclear whether the glomerular deposition of C1q is in response to the deposition of immunoglobulins or immune complex, or the deposition represents non-specific trapping of C1q accompanying the increased glomerular trafficking associated with proteinuria. [16] Our patient had no history or clinical manifestations of clinical conditions that can be associated with secondary C1q glomerular deposition, such as systemic infection or connective tissue autoimmune diseases.

Said et al [17] described 24 renal allograft biopsies with dominant or co-dominant glomerular C1q deposition. None of the patients were diagnosed with C1q nephropathy in the native kidney or had features of SLE. The indication for biopsy was surveillance in 63% of the patients or graft dysfunction in 37%. On follow-up of ten patients without concurrent allograft rejection, most had stable creatinine with no or stable proteinuria, and none lost their graft. The authors concluded that C1qdominant mesangial deposition in the renal allograft is a morphological pattern with no apparent clinical significance in the majority of patients. The patient in the current case had neither hematuria nor significant proteinuria at the time of presentation and follow-up period.

In the current case, of course, the presence of clinically undetected pre-existence C1q nephropathy that was superimposed by hemosiderosis and AIN is a possibility. The possible contribution of PNH to C1q deposition is intriguing. Calreticulin (CRT) is a multifunctional protein present in the endoplasmic reticulum and cell membranes of a variety of cells, including RBC, and is involved in a number of cellular functions. It is considered to be a C1q receptor on neutrophils and has neither a transmembrane domain nor a GPIanchor attachment site and must utilize an adaptor molecule to attach to the plasma membrane. CD59 is found to be a major adaptor for CRT and association with CD59 deficiency, and CRT deficiency was reported by Ghiran et al. [18] In addition, it was proposed that CRT stabilizes the RBC membranes to restrict osmotic lysis and inhibit perforin lytic activity on cell membranes. [19] Binding CRT to C1q inhibits hemolysis of IgM-sensitized erythrocytes. [19] In PNH, absence or reduction of expression of CD59 will be associated with decreased C1q-CRT interaction. It is possible that, in our patient, this might have resulted in intravascular hemolysis and was responsible for glomerular C1q deposition due to the excess of unbound C1q in the circulation. The long-term clinical outcome for this C1q deposition is unknown. Furthermore, the mechanism of C1q deposition in PNH, and its diagnostic significance and clinical outcome are not clear and need further investigations to explore the possible pathological relationship.

Another observation worth mentioning is the presence of co-dominant mesangial deposition of IgG. Glomerular mesangial deposition occurs in various types of primary and secondary glomerulonephritis. In the current case, the possibility of IgG glomerulonephritis as a differential diagnosis should be considered. IgG glomerulonephritis/nephropathy is a very rare type of primary glomerulonephritis that is characterized by exclusive or predominant mesangial IgG deposits and is often associated with mesangial deposition of complement components, mainly C3 and C1q. [20] The deposition of C1q is present in most cases and can be co-dominant or rarely dominant. [21] Furthermore, the light microscopic histological features of IgG nephropathy can be similar and show significant overlapping with those of C1q nephropathy, leading some investigators to suggest IgG/C1q nephropathy as a tentative diagnosis. [21] Noticeably, in one series, C3 deposition was identified in all 14 patients with IgG glomerulonephritis, [20] while C3 deposition was reported in 52.6% (ten of 19) [12] and 67% (16 of 67) of patients with C1q nephropathy in two series. In our case, C3 deposition was not detected.

In summary, we described an unusual case with various clinical and pathological findings that include undiagnosed PNH, acute renal failure, renal hemosiderosis, herb-induced AIN and acute bone marrow toxicity and incidental co-dominant C1q mesangial deposition, and discussed the possible relationship between them.

Conflict of Interest: None declared.

   References Top

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Said SM, Cornell LD, Valeri AM, et al. C1q deposition in the renal allograft: A report of 24 cases. Mod Pathol 2010;23:1080-8.  Back to cited text no. 17
Ghiran I, Klickstein LB, Nicholson-Weller A. Calreticulin is at the surface of circulating neutrophils and uses CD59 as an adaptor molecule. J Biol Chem 2003;278:21024-31.  Back to cited text no. 18
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Correspondence Address:
Dr. Khalid S Alkhairy
Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, King Saud University for Health Sciences, P. O. Box 22490, Riyadh 11426
Saudi Arabia
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DOI: 10.4103/1319-2442.157384

PMID: 26022031

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1]


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