Case 1
A 56-year-old female patient, who had previously undergone mechanical aortic valve replacement surgery nine months ago and was prescribed warfarin as post-surgery treatment, was admitted to the hospital due to the occurrence of gross hematuria six days before hospitalization. Additionally, her creatinine levels exhibited a rapid increase from 120.5umol/L to 207.5μmol/L within three days.
Upon admission, the patient's vital signs were recorded as follows: blood pressure of 132/74 mmHg, heart rate of 83 beats per minute, and temperature of 36.3°C. Subsequent laboratory analysis revealed the following findings: creatinine level of 167.8μmol/L, eGFR of 30.5ml/min.1.73m2, blood urea nitrogen/creatinine ratio of 17.9, albumin level of 39.6g/L, hemoglobin level of 10.4 g/dl, white blood cell count of 6.6×109/L, platelet count of 238×109/L, and an INR value of 2.08. The urinary test results indicated the presence of urinary protein(+) and urinary occult blood(3+).Microscopic examination of the urine sediment revealed the presence of 20-40 red blood cells per high-power field, with a deformation rate of 70%. The quantification of urinary protein over a 24-hour period was measured at 0.69g. Additionally, the C-reactive protein level was found to be 8.49mg/L (normal range 0-5mg/L). Other tests including serum immunoglobulins (IgA, IgG, and IgM), Antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile all yielded negative results. Serum protein electrophoresis and serum immunofixation yielded negative results. Renal ultrasound examination indicated a right kidney size of 9.4 cm and a left kidney size of 9.9 cm, both exhibiting normal cortical thickness.
A renal biopsy was performed on the 7th day after admission. Immunofluorescence analysis demonstrated a 3+ intensity of IgA and a 2+ intensity of C3, primarily displaying a coarse-grained pattern within the mesangial region.Upon light microscopy examination, it was observed that the renal tissue contained a total of 21 glomeruli. Among these, one glomeruli exhibited ischemic sclerosis, accounting for approximately 4.8% of the total, while two glomeruli displayed ischemic shrinkage, representing approximately 9.5%. The remaining glomeruli showed mild mesangial cell proliferation and an increased mesangial matrix. Furthermore, the renal capsule displayed one large cell crescent, one small fiber crescent. Renal interstitial fibrosis, which accounts for approximately 35%, and renal tubular atrophy were observed. Tubular cross sections displayed a notable presence of red cell casts.Perl’s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells. Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. Additionally, a mild thickening of the renal arteriole wall was observed. Electron microscopy (EM) demonstrated a mild increase in the proliferation of glomerular mesangial cells and matrix, accompanied by the accumulation of clustered electron-dense substances within the mesangial region and fusion of a majority of epithelial foot processes. (Figure 1) Consequently, the patient was diagnosed as WRN with focal proliferative IgA nephropathy.The patient continued to receive warfarin anticoagulant, and were prescribed a supplementary treatment regimen comprising oral sodium bicarbonate, prednisolone at a daily dosage of 20mg, and cyclophosphamide at a dosage of 50mg every other day. Before being discharged, the patient's creatinine level was assessed and found to be 156.6μmol/L. During a subsequent follow-up after a two-month period, the patient's creatinine level had decreased to 109.2μmol/L, and the urine protein quantification was recorded as 119.7 mg/24 hours. (Figure 2)
Case 2
A 63-year-old male patient, who has been diagnosed with hypertension for the twenty years, underwent a partial nephrectomy for left renal clear cell carcinoma five years ago. Additionally, five and a half years ago, the patient underwent Bentall+Sun's surgery, which involved aortic root replacement, total aortic arch replacement, and stent elephant nose surgery, for managing type A aortic dissection. Following the surgery, the patient was prescribed warfarin due to the replacement of a mechanical valve. The patient was admitted to the hospital due to persistent gross hematuria for a duration of forty days and an increase in creatinine levels for one month.
Upon admission, the patient's vital signs were recorded as follows: blood pressure of 192/124 mmHg, heart rate of 76 beats per minute, and temperature of 36.3°C. Subsequent laboratory analysis revealed a creatinine level of 169.9μmol/L (which was within the normal range one year ago), eGFR of 37.2ml/min.1.73m2, a blood urea nitrogen/creatinine ratio of 14.1, albumin level of 39.5g/L, hemoglobin level of 13.3 g/dl, white blood cell count of 6.27×109/L, platelet count of 204×109/L, and an INR of 2.69. The urinary test indicated the presence of urinary protein (2+) and urinary occult blood (3+). The microscopic analysis of urine sediment reveals full of red blood cells in high-power field, exhibiting an 80% deformation rate. Urinary protein quantification was 3.06g/24hours. The serum IgA level was measured at 4.55g/L, falling within the normal range of 1.0-4.2g/L. Conversely, IgG and IgM levels were found to be within the normal limits. Results for antinuclear antibody, acute hepatitis panel, double-stranded deoxyribonucleic acid, rheumatoid factor, complement levels (C3 and C4), and antineutrophil cytoplasmic antibody profile were all normal. Negative results were obtained from serum protein electrophoresis and serum immunofixation. Renal ultrasound revealed a right kidney size of 11.8 cm and a left kidney size of 11.5 cm, both demonstrating normal cortical thickness.
During the patient's hospitalization, his creatinine levels reached a maximum of 231.4μmol/L. A renal biopsy was performed on the fourteenth day after admission. The subsequent immunofluorescence analysis demonstrated a 2+ intensity of IgA and C3, accompanied by segmental mesangial granular deposition. Under the observation using light microscopy, it was found that among the total of 21 glomeruli, approximately 33.2% (7 glomeruli) exhibited ischemic sclerosis, while approximately 14.3% (3 glomeruli) displayed ischemic shrinkage. The remaining glomeruli demonstrated mild mesangial cell proliferation and an increase in mesangial matrix, accompanied by segmental exacerbation and occasional endothelial cell proliferation. One glomerulus exhibited segmental sclerosis. Renal interstitial multifocal fibrosis, accounting for approximately 60%, was accompanied by a significant infiltration of mononuclear cells, occasional eosinophils, and plasma cells. Furthermore, the presence of granular and vacuolar degeneration in the renal tubular epithelial cells, as well as multifocal renal tubular atrophy, was observed. Additionally, the detachment of brush-like edges of renal tubular epithelial cells, flattened epithelial cells, and the presence of a small amount of protein tubular type, a large amount of red blood cell tubular type, and a small amount of exfoliated cells in the lumen were noted. Moreover, evidence of epithelial cell regeneration was observed, along with the disappearance of normal structures in numerous renal tubules. Perl’s Prussian Blue stain diaplayed hemosiderin deposits in the tubular epithelial cells Immunohistochemical stain for cytokeratin AE1/AE3 highlights distal tubules with occlusive RBC casts. EM demonstrated mild mesangial cell proliferation and an augmentation of mesangial matrix within the glomerulus. Moreover, the deposition of blocky electronic dense substances can be observed in the mesangial and paramesangial regions, along with the fusion of segments of foot processes. Additionally, an increase in lysosomes within renal tubular epithelial cells and partial detachment of microvilli have been noted. Lastly, renal interstitial edema is present. (Figure 3) The patient was diagnosed as ARN with focal proliferative IgA nephropathy.
The patient’s anticoagulation therapy with warfarin was continued, along with a daily dosage of 20mg of prednisolone and an oral dosage of 50mg of cyclophosphamide every other day. Before being discharged, the patient's creatinine level was assessed at 213.5μmol/L. During a subsequent follow-up after four months, the patient's creatinine level had decreased to 125μmol/L, and the quantification of urine protein was recorded at 600mg/24hours.(Figure 4)
Literature review
In previous literature, a total of ten cases of WRN confirmed by renal biopsy in patients with prosthetic valves were summarized [7-13]. The age range of the cases was between 50 and 76 years, with a time interval of 11 months to 26 years from the initiation of oral warfarin administration to the onset of WRN. Six of them had elevated baseline creatinine levels. The INR values varied from 1.36 to 6.08, and two patients had an INR<3 upon admission. All the cases exhibited progressive elevation in creatinine levels and presence of hematuria. Among these cases, eight presented with gross hematuria, while the remaining two cases showed microscopic hematuria. Nine cases showed renal function progression. Furthermore, six cases were complicated by the presence of IgAnephropathy. Steroids were administered in five cases, and four cases initiated dialysis treatment upon the onset of the WRN. Ultimately, among these four cases, three remained on dialysis, while one case experienced improved renal function and no longer dependent on dialysis. Whereas it is noteworthy that the three cases who failed to recover renal function had elevated baseline creatinine levels, ranging from 180-430μmol/L. The remaining six cases showed varying degrees of improvement in renal function. (Table 1)