Significant association between renal function and amyloid-positive area in renal biopsy specimens in AL amyloidosis

AL amyloidosis is a severe systematic disorder that often affects a systemic symptoms or signs [1]. Amyloid deposition is believed to occur insidiously with age, if patients have had those precursor proteins for long time. Small amounts of amyloid deposition have no ill effects on any organ function, while excessive deposition of amyloid into systemic organs can be potentially fatal [2]. The clinical features of amyloidosis vary by the organ affected. Cardiac amyloidosis causes heart failure [3]. Gut involvement causes disturbances of intestinal movement developing to malabsorption, perforation, hemorrhage, and obstruction [4]. Amyloid deposition into peripheral and autonomic nerves reveals sensory disturbance and orthostatichypotension [4]. Carpal tunnel syndrome is often induced by amyloid deposition into tendons in the wrist joint and is a sensitive clue for systemic amyloidosis when it is bilateral [5]. Skin involvement takes the form of papules, nodules, and plaques. Cutaneous amyloidosis can be a risk factor for non-healing ulcer in elderly persons [6]. The kidney is a major target organ for systemic amyloidosis that often affects the kidney including proteinura, and elevated serum creatinine (Cr). Nephrotic syndrome is present in more than one fourth of patients at the time of diagnosis [7]. The prognosis of renal amyloidosis is generally poor, in AL amyloidosis, mainly because conventional treatments with the previous agents were unable to stop the decline of renal function [8–10]. Many patients will develop end-stage renal failure (ESRF). Additionally, it is generally considered that the quality of life under dialysis is poor with a high rate of mortality [11].

In renal biopsy specimen, histopathologic classification, scoring and grading system for renal amyloidosis was proposed [12]. However, the correlation of these scoring and grading and clinical parameters such as urinary protein or serum creatinine was not fully investigated yet. No clear relationship between the amyloid deposition evident in renal biopsy specimens and the severity of clinical manifestations has yet been demonstrated [12]. Furthermore, the correlation between the amount of amyloid deposits and clinical parameters is not known. In the present study, we investigated the clinical utility of the area of renal biopsy specimens occupied by amyloid and its correlations with various clinical parameters.

AL amyloidosis can be classified as either primary amyloidosis or secondary to multiple myeloma, on the basis of the number of plasma cells in the bone marrow and/or the presence or absence of skeletal lesions that frequently involve the kidneys [15]. Once the symptoms of amyloidosis have manifested, disease progression is usually rapid [14]. Kyle, et al. reported that, based on a multi-variate analysis of 168 AL amyloidosis patients, renal function was a predictor of survival 1 year after diagnosis [15]. Other study demonstrated that the long-term prognosis of renal amyloidosis is significantly poorer if Cr concentration at the time of biopsy is 1.3 mg/dl or more [16]. Additionally the progression of renal pathological damage due to amyloid deposition expected a short renal survival time and poor individual survival [16]. In a study of 63 AL amyloidosis patients with renal amyloidosis found that high Cr concentration at biopsy and interstitial and/or vascular damage by amyloid deposition accelerated the progression of renal dysfunction [17]. The findings of the study confirmed that both renal function and interstitial damage at biopsy were predictive factors for prognosis of survival, but mesangial expansion was not [18]. In AL amyloidosis, renal amyloid deposits were frequently deposited in order. Amyloid deposits were initially deposited inside the glomrular basement membrane and mesangium is a principal site of amyloid deposition in glomeruli. Amyloid deposits may occur in segmental, diffuse mesangial, nodular, and pure basement membrane pattern [19]. Segmental amyloid deposits are small, discrete, and confirmed to the masangium without forming nodules. Although this form is so small but it is pointed out that these small deposits can be associated with massive proteinuria. In our study, these small nodules were included in the amyloid positive area, although these small nodules might be the reason of massive proteinura. This might be the reason that Log₁₀%amyloid was not correlated with urinary protein. In general, the tubular interstitial component may be variably affected. The tubules may show nonspecific findings or vacuolization and damage. Interstitial and peritubular deposits of amyloid are seen in approximately 50% of cases. Medullary amyloid deposits are more frequent and more extensive [20].

In renal vessels, they are often involved, with arteriolar deposits being most frequent, followed by deposits in arteries, peritubular capillaries and veins. Vascular deposits frequently coexist with glomerular amyloid, but the extent of vascular amyloid deposition is unrelated to the pattern of glomerular involvement [21]. These morphological courses of renal depositions are considered the progression of renal involvement may reflect the clinical parameters.

Our results showed the significant correlation between Log₁₀%amyloid and eGFR, but Log₁₀%amyloid was not correlated with Ccr, because the dissociation was existed between eGFR and Ccr. The international standard method to measure glomerular filtration rate (GFR) is inulin clearance (Cin). However, Cin was not applied in clinical practice in Japan. Ccr is frequently made use of measurement of renal function, because of its simple method. The dissociation between Ccr and GFR is known in previous studies [22]. Usually Ccr shows higher than the value of GFR. In Japanese, approximately the revel of Ccr was 20% higher than the level of Cin [23]. In our results of Table 1 showed the dissociation between Ccr and eGFR. Ccr is about 8% higher that eGFR. Therefore, eGFR is considered to be closer to the GFR level than Ccr. Log₁₀%amyloid may correlate as true renal function of GFR. Recently, we revealed that there was a significant correlation between the area of amyloid deposition in renal tissue and parameters of renal function in AA amyloidosis associated with rheumatoid arthritis and the results were similar to this study [14]. In AA amyloidosis, we also revealed that the treatment of biologics for rheumatoid arthritis reduce the amyloid deposits in gastroduodenal biopsy specimen [24]. Some cases in these AA amyloidosis patients reduce Cr and elevated Ccr were observed for these patients. In AL amyloidosis, specific therapy was significantly prolongs survival and slows the progression of renal disease [25]. Repeated biopsy of kidney was difficult in practice but fluctuation of Cr of eGFR may reflect the amount of deposition of renal tissue in AL amyloidosis patients. Recently, the serum free light chain (sFLC) concentration has been shown to be a reliable predictor of the response and progression of multiple myeloma. However, only one-third of the patients in our study underwent sFLCs measurement, and because of the large number of missing data, we did not include this parameter in the study.

In conclusion, there is significant association between amyloid positive area in renal tissue and renal function, especially Cr and eGFR. Urinary protein and Ccr was an important marker in renal amyloidosis, but not correlated with amyloid-positive area. Medication with diuretics, ACE, ARB or steroid at the time of renal biopsy was not correlated with the area of amyloid positivity in renal tissue. The level of Cr and eGFR may be a marker of the amount of amyloid in renal tissue. As this was a cross-sectional study, further follow-up of patients for a longer time to observe the progression of CKD in relation to the area of amyloid positivity will be necessary to confirm our observations.