A 58-year-old man was referred to our hospital in January 1989 for an evaluation of weight gain, nephrotic range proteinuria, and renal dysfunction. He had no relevant medical history. On examination, he had a temperature of 36.5 C, a pulse rate of 76/min, a respiration rate of 14/min, and a blood pressure of 170/100 mmHg. Pitting edema of the lower extremities was noted bilaterally.
Laboratory findings were as follows: serum albumin was 2.9 g/dL, total protein was 5.0 g/dL, urea nitrogen was 27 mg/dL, and the serum creatinine was 1.8 mg/dL [(estimated glomerular filtration rate (eGFR) was 32 mL/min]. Antinuclear antibody was negative. Serum C3 was 50 mg/dL, C4 was 32 mg/dL, and CH50 was 34 U/mL. The serum level of immunoglobulin G (IgG) was 669 mg/dL, with an IgA level of 122 mg/dL and IgM level of 87 mg/dL, and there was no monoclonality. The serum monoclonal protein and urinary Bence Jones protein (using electrophoresis method) were negative. Urinary protein excretion was 4.2 g daily, and the sediment contained 1 to 5 erythrocytes per high-power field. Although bone marrow aspiration showed a slight increase of mature plasma cells, even showing positivity for kappa and lamda (4.2% of nucleated cells), there were no abnormal findings on the smear and no osteolytic lesions were identified by a full skeletal survey. Therefore, he did not meet the criteria for multiple myeloma or monoclonal gammopathy of undetermined significance.
Renal biopsy was performed in January 1989 and LM revealed global sclerosis in 2/25 glomeruli. Mild to moderate expansion of the mesangial matrix and marked thickening of the glomerular basement membrane (GBM) with a double contour were noted evenly on almost all non-sclerotic glomeruli in sections with periodic acid-Shiff (PAS) and periodic acid-silver methenamine (PAM) staining (Fig. 1A). Congo red staining was negative. Immunofluorescence microscopy (IF) showed strong staining for kappa light chain in the mesangial region and along the GBM, but weakly and partially along the tubular basement membrane (TBM) (Fig. 1B). There was no staining for lambda light chain, IgG, IgA, and IgM. Electron microscopy (EM) revealed massive subendothelial dense deposits and edema of the GBM and dense deposits on inner zone of TBM, as well as mesangial dense deposits (Fig. 1C). No microfibrillar structures were observed. Atrophy of the tubules and fibrosis of the interstitial space were minute. Sclerotic change of small arteries was mild. These clinical and histological features confirmed the diagnosis of kappa-type LCDD.
Treatment was started with prednisolone (30 mg, 3 times weekly) and azathioprine (50 mg daily) was added in 1989. Azathioprine was replaced by bredinine (25 mg daily) within two years because of progressive anemia (hemoglobin 6.2 g/dL), but his proteinuria increased to 5.8 g daily. In 1991, melphalan was started at a dose of 6 mg administered 2 days per week together with prednisolone [methylprednisolone (MP) therapy]. The dose of melphalan was soon tapered to 4 mg, and it was later reduced to 2 mg in 1995, after which it was discontinued in 2001. Prednisolone was decreased to 25 mg 3 times weekly in 1996, and was tapered to a cycle of 10 mg-0 mg-15 mg-0 mg in 1999. His proteinuria gradually improved and remained at a level of 0.5 to 1.5 g per day until 2005. The serum monoclonal protein and urinary Bence Jones protein remained negative over time. Serum creatinine also remained around 1.5 to 2 mg/dL. In 2005, right nephrectomy was performed because of renal cell carcinoma, after which his creatinine deteriorated to 3.5 mg/dL and hemodialysis was started 1 year later because of over-filtration for the remnant kidney.
Antihypertensive agents such as calcium antagonist and angiotensin converting enzyme inhibitors were administered to treat hypertension until the initiation of hemodialysis after his first admission. Until 2007, no serum monoclonal protein or urinary Bence Jones protein (using electrophoresis method) were detected, though a significant elevation of the serum kappa light chain was detected in comparison to that of the lambda chain, while the free light chain in the serum and urine was not considered to be applicable.
Sequential renal biopsies were performed in 1989 (1st), in 1991 (2nd) (at Cre of 2.0 mg/dL), in 1995 (3rd) (at Cre of 1.8 mg/dL), in 2001 (4th) (at Cre of 1.8 mg/dL), and surgical nephrectomy was done in 2005 (5th) (at Cre of 2.4 mg/dL).
The second renal biopsy (1991) was performed because of an exacerbation of this disease and therapeutic reexamination. LM containing 22 glomeruli did not show any global sclerosis, but multiple marked nodules were observed which had formed due to the expansion of mesangial and subendothelial lesions (Fig. 3A), while EM showed an increase of the mesangial and subendothelial dense deposits of GBM and thickening of TBM (Fig. 3B), and IF showed strong staining for the kappa light chain along TBM in addition to glomeruli (Fig. 3C). Tubulointerstitium and the small arteries showed findings similar to the LM findings identified at the 1st biopsy.
The third renal biopsy (1995) was done to check the time of tapering of MP therapy. LM revealed global sclerosis in 68/82 glomeruli. Atrophy of tubules and fibrosis with inflammation of interstitial space became definite around glomeruli with global sclerosis, and small arteries became sclerotic and hyalinotic. Each of the non-sclerotic 14 glomeruli demonstrated a marked reduction of the mesangial nodules and thinning of the GBM (Fig. 4A). EM also revealed a marked reduction of the subendothelial lesions of GBM, mesangial lesions and inner zone lesion of GBM, with an appearance of new electron-lucent areas (Fig. 4B).
A fourth renal biopsy (2001) was done to check the time of further tapering of MP therapy. LM showed global sclerosis in 26/34 glomeruli. The changes in the tubulointerstitium and small arteries were similar to those observed after the 3rd biopsy. Each of non-sclerotic 8 glomeruli revealed a complete resolution of the nodular lesions, and had a nearly normal appearance by LM (Fig. 5A) as well as EM (Fig. 5B). However, strong staining for kappa light chain was still detected along the GBM, although the staining of the kappa light chain along TBM had become obscure (Fig. 5C).
A surgical specimen of the resected kidney (2005) showed sclerotic regions in the glomeruli, moderate to severe tubular atrophy, and fibrosis of the tubulointerstitium was clearly distinguished and it was separate from the nearly normal region, and it occupied approximately 80% of the total renal cortical region, which was similar to the LM and IF findings observed in the fourth biopsy, which was considered to probably be due to long-term hypertension and oral steroid therapy, and hypertensive ischemia of the small renal arteries, Moreover, his sequential renal histology also showed a deterioration of chronic renal damage with the development of arterio-sclerotic changes associated with long-term systemic hypertension. The accumulation of the meningeal matrix and thickening of the GBM on non-sclerotic glomeruli had both slightly increased (Fig. 6), presumably because of the termination of the MP therapy.