Renal hemosiderosis and rapidly progressive glomerulonephritis associated with primary hemochromatosis

Abstract

Hereditary hemochromatosis leads to the accumulation of iron in many organs including the liver, spleen and heart and results in injury and dysfunction of these organs. On the other hand, iron accumulation and functional impairment in kidney is extremely rare. We report a 61-year-old male patient with hereditary hemochromatosis, in whom the renal function was deteriorated rapidly. Renal biopsy revealed crescentic glomeruli and hemosiderin accumulation in tubular epithelial cells.

• Cardiac disorders
• crescentic glomerulonephritis
• diabetes mellitus
• hereditary hemochromatosis
• liver disease
• skin pigmentation

Introduction

Major clinical manifestations of the iron accumulation in primary hemochromatosis (PH) include liver disease, skin pigmentation, diabetes mellitus (DM), arthropathy, male impotence, and cardiac disorders.1 However, hemochromatosis-associated renal involvement is extremely rare. There are two case reports in the literature on hemochromatosis-associated IgA nephropathy,2,3 and both of these patients have been considered as secondary IgA nephropathy associated with liver disease. Furthermore, there are several human cases developing renal hemosiderosis associated with hemochromatosis.4,5 This is the first case report concerning a hemochromatosis-associated rapidly progressive glomerulonephritis (RPGN) case that do not meet the RPGN cases previously reported in the literature.

Case report

A 61-year-old male was admitted to a medical unit with head/neck pain in March 2011. Neurological examination was normal; but impairment of renal functions was observed. The patient was referred to our hospital. He was using 50 mg of metoprolol for 15 years because of the existing arrhythmia. He had no history of systemic disease and was not using any medication other than metoprolol. At the time of admission, blood pressure was 160/90 mm Hg, body temperature was 36.3 °C, urinary output was 1200–1400 cc/d, and physical examination revealed no pathological sign. Laboratory test results were as follows: hemoglobin 17 g/dL, hematocrit 50.7 (%), leukocyte 5.3 × 10³ (64.2% neutrophil, 22.1% lymphocyte, 8.7% monocyte, 2.2% eosinophil, 0.4% basophil), platelet count 439 × 10³, reticulocyte 0.12% (0.8–2.5), haptoglobulin 256 mg/dL (30–200 mg/dL), and direct coombs negative. Urine analysis revealed (+++) protein, 64/HPF erythrocyte, 3/HPF leukocyte, 2.04 g/d of proteinuria, 70–80% of erythrocytes were dysmorphic and no cylinders in urine sediment examination. Blood urea nitrogen (BUN) and serum creatinine (Scr) were 77 mg/dL and 3.73 mg/dL at the time of the admission, respectively. Scr was 4.1 mg/dL on 10.03.2011, 4.66 mg/dL on 14.03.2011 and 5.7 mg/dL. The results of laboratory tests after a week were as follows; BUN: 120 mg/dL, Scr: 6.56 mg/dL, Na: 134 mEq/L, K: 4.7 mEq/L, Ca: 8.7 mg/dL, P: 6.4 mg/dL, total protein 7 g/dL, albumin 3.7 g/dL, liver function tests normal, C-reactive protein: 1.05 mg/dL, sedimentation: 34 mm/h, thyroid function tests normal, Ig G: 1120 mg/dL, IgA: 220 mg/dL, IgM: 180 mg/dL, complement C3: 178 mg/dL, complement C4: 39.4 mg/dL, anti-nuclear antibody was negative, p ANCA, c ANCA and antiglomerular basement membrane antibodies were negative, hepatitis B and C serology and HIV antibody were negative, serum iron 122 mg/dL, serum transferrin saturation 57.75%, and ferritin 518 ng/mL. Electrocardiography, echocardiography and gastrointestinal system endoscopy findings were normal. Ultrasonography showed that both kidneys were normal in size and there was no organomegaly. T1- and T2-weighed MRI images showed diffusely hypointense liver and spleen. Genetic analysis revealed homozygosity for the C282Y mutation which is the most common genotype responsible for clinical iron overload. There was no history of oral iron and vitamin C therapy, alcohol consumption and blood transfusion. Any hematological diseases that can result in thalassemia or hemolytic anemia were excluded. These findings suggested the diagnosis of hereditary hemochromatosis gene (HFE)-associated hemochromatosis.

Percutaneous renal biopsy was performed. There were a total of 52 glomeruli in the kidney tissue and of them, six showed cellular, seven fibrocellular, four fibrous crescents, and five glomeruli were globally sclerotic (Figure 1). Capillary loops were compressed by crescents. There was minimal increase in cellularity and mesangial matrix in some of the glomeruli without crescent. Zone-by-zone atrophic changes in the tubules and scattered, increased number of mononuclear cells in the interstitium were seen. Brown-colored pigment was present diffusely in tubular epithelium and it was stained with Prussian blue (hemosiderin) (Figures 2–3). Crystal violet and Congo red stains for the assessment of the presence of amyloid were negative. Immunofluorescence studies revealed focal and weak staining with IgM and fibrinogen in the mesangium; IgG, IgA, C3, and C1Q were negative. The patient was diagnosed as renal hemosiderosis and crescentic glomerulonephritis associated with PH.

Figure 1. Glomerulus with fibrocellular crescent at right and with early cellular crescent at left (H&E × 100).

Figure 2. Widespread hemosiderin deposition in tubular epithelial cells (Prussian blue stain ×40).

Figure 3. Glomerulus with fibrous crescent and tubular epithelial cells showing hemosiderin deposition (Prussian blue stain ×200).

The patient was treated with 15 mg/kg/d intravenous (IV) pulse methylprednisolone for 3 d, followed by 1 mg/kg/d of oral prednisolone. Serum creatinine value was reduced to 2.9 and 2.6 mg/dL on the days 15 and 30, respectively. On the post-treatment day 45, the patient attended to the emergency department with dyspnea and died due to respiratory arrest; postmortem biopsy was not performed.

Discussion

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by the findings of glomerular disease in the urine and a rapid decline in renal function in days, weeks or months. Morphologically, it is characterized by excessive crescent formation. There are four subtypes of RPGN – anti-glomerular basement membrane disease (type 1), immune complex RPGN (type 2), pauci-immune or ANCA-associated RPGN (type 3), and the mixed type showing the features of type 1 and 3 (type 4). In addition, there is another form, idiopathic RPGN, which could not be classified in any of the four groups.6

In this article, we report the first case of RPGN associated with hemochromatosis. Hemochromatosis associated renal involvement is extremely rare. There are two cases of hemochromatosis-associated IgA nephropathy in the literature, with gradual impairment of the renal function in the case reported by Gouet et al.3 and a rapidly progressive course in the case reported by Nakayama et al.2 Both of these patients have been considered as secondary IgA nephropathy associated with liver disease. IgA nephropathy associated with liver disease is the most common form of secondary IgA nephropathy.7 Dysfunction of hepatic and splenic clearance of IgA immune complexes is the possible pathogenic mechanism in hepatic IgA nephropathy.8 Patients with hepatic IgA nephropathy may be asymptomatic or have microscopic hematuria, proteinuria and, in some cases, mild renal dysfunction.9 In this context, if hemochromatosis is the underlying disease in secondary IgA nephropathy, it should be considered that renal function can deteriorate rapidly. In our case, no immune complex deposition was present and RPGN was developed independently from secondary IgA nephropathy; to our knowledge, this presentation associated with PH is the first in the literature.

Renal hemosiderosis that is usually secondary to chronic intravascular hemolysis is an incidental finding in postmortem biopsies and it is not considered as leading to significant functional impairment.10,11 Clinical course of idiopathic hemochromatosis varies depending on the region involved and amount of iron accumulation.4,5 Okumura et al.5 reported that accumulation of iron in distal urinary tubular epithelium leads to nephrogenic diabetes insipidus, and Marble et al. 4 reported a small amount of iron accumulation in 6 of 15 autopsy cases with hemochromatosis with no severe renal dysfunction due to lack of diffuse hemosiderin accumulation. Because there was a small amount of hemosiderin in the histopathologic examination of PH cases, Nakayama et al. have explained the rapid renal dysfunction by secondary IgA nephropathy associated with renal hemosiderosis. In our case renal functions were deteriorated more rapidly in our case than the case reported by Nakayama et al. (Scr doubling time of 1 week vs 40–45 d). In the present case, the rapid deterioration in renal function was thought to be caused by diffuse iron accumulation in the tubular epithelial cells in addition to crescent formation.

In conclusion, the site and amount of iron accumulation determine the severity of renal dysfunction in cases with renal involvement associated with PH. In addition, cases with a rapid progressive course are extremely rare.

Declaration of interest

The authors have declared that no conflict of interest exists.