Renal Siderosis in Donor Allograft: Pathologic and Clinical Sequelae



Transplantation of a cadaver kidney with marked siderosis and its outcome has not been reported. Increasing use of marginal kidneys has become common practice to expand the donor pool to meet the growing demand and will lead to increased recognition of kidney disease in cadaver donors with an unknown effect on graft outcome. This is a case report of a recipient of a cadaver kidney with marked siderosis monitored by surveillance biopsies and evaluated by clinico-pathological correlation. The recipient continued to have transplant kidney function, and a surveillance biopsy shows the natural course of the pathologic resolution of renal siderosis.

Case Report

A 73-year-old woman with end stage renal disease, diabetes and hypertension presented for renal transplantation. Available organ was from a 63-year-old man with a medical history of mechanical heart valve replacement for many years (mitral and aortic) and an embolic stroke. The organ had been rejected for transplantation at other centers. Final donor BUN and creatinine values were 27 mg/dL and 1.0 mg/dL, respectively.

The kidney was brown in color to the naked eye examination and flushed well with cold University of Wisconsin solution before transplantation. Pathologic evaluation of the graft was performed before transplantation, using Banff ′97 (1) schema. An approximate hemosiderin quantitation was performed on Prussian blue-stained sections using the same method originally described by Scheuer et al. (1,2) for the quantitation of hemosiderin in liver biopsies, with grade 0 being negative and grades 1, 2, 3 and 4 representing increasing amounts of stainable hemosiderin. Microscopically, chronic changes of global glomerulosclerosis (10%), fibrosis and arterial sclerosis were noted [ci1, cv1, Banff ′97 (1)]. The tubular epithelium showed severe iron overload (4+/4+) (Figure 1A). The iron was distributed predominantly in the proximal tubular epithelial cells and the absolute level was quantified from paraffin-embedded tissue at 3985 μg/g of dry weight. The organ was utilized for transplantation. Cold ischemic time was 15 h and warm ischemic time was 25 min. The clinical assumption was that the kidney would function in the recipient because it was functioning well in the donor and the iron would slowly be removed from the graft in a recipient who did not have iron overload. The immunosuppression was basiliximab induction, and maintenance with cyclosporine, mycophenolate mofetil and prednisone. The kidney functioned immediately and the recipient did not require dialysis support in the post transplant period. Two months post transplant a biopsy for clinical rejection showed 1A rejection (Banff ′97) and decreased iron (3+/4+). The chronic fibrosis, vascular and tubular grades were unchanged since transplantation (Figure 1B). One-year protocol biopsy showed quantitatively decreased tubular epithelial iron (2+/4), occasional interstitial macrophages containing iron pigment and no rejection. The chronic fibrosis, vascular and tubular grades were unchanged since transplantation (Figure 1C). Two-year protocol biopsy showed borderline rejection and only focal staining for iron in the proximal tubular epithelial cells. The fibrosis, vascular and tubular atrophy grades were unchanged since transplantation. The 1 and 2-year serum creatinine were 2 mg/dL and 2.8 mg/dL, respectively. Although no specific interval change in chronic indices was noted, the slowly increasing creatinine from 2 mg/dL to 2.8 mg/dL was attributed to chronic allograft nephropathy. No clinical evidence of significant tubular dysfunction such as glycosuria, salt wasting, renal tubular acidosis, and aminoaciduria above and beyond that seen in the general renal transplant patient population was noted. The patient was not significantly anemic during the surveillance period with hemoglobin ranging from 10.5 mg/dL to 12.7 mg/dL.

Figure 1.

Low-power view of donor kidney with mild chronic changes (global glomerulosclerosis, fibrosis, tubular atrophy and vascular sclerosis) (H&E, × 40).


According to the U.S. Renal Data System the number of patients with kidney failure will show a remarkable increase by 2010 (3). The UNOS waiting list for cadaveric kidney transplantation is rising at a rate of 20% per year and will include an estimated 95 000 patients by 2010 (4,5). The need to maximize organ donation cannot be understated.

The problem of organ shortage has led to an expansion of the acceptable organ pool, so that now 30% of kidney transplants are from ‘marginal donors’ (6). Randhawa et al. (7) discard donor kidneys only when glomerulosclerosis is >20% or there is more than grade 1 arteriosclerosis or interstitial fibrosis. The kidney work group (8) noted a discard rate of 50% for kidneys recovered from donors age older than 60 years.

Renal siderosis was first described in 1925 by Lubarch (9) and was well documented and repeatedly described during the following 50 years. The most common causes of severe renal siderosis are repeated blood transfusion, recurrent hemolysis and hemochromatosis. The pattern of renal tubular deposition of hemosiderin differs between hemosiderosis and hemochromatosis, with proximal tubular involvement in hemosiderosis and Henle's loop involvement in hemochromatosis. Mild to moderate renal siderosis does not produce significant pathology while severe renal siderosis results in tubular atrophy and interstitial fibrosis. With interstitial fibrosis, macrophages containing iron are present. In Marchiafava (10) anemia as well as in patients with an excessive number of blood transfusions, cases of contracted, atrophic kidney have been described. It has been suggested that iron overload is responsible for renal dysfunction in alpha and beta-thalasemia (11). In the urine of these patients with renal siderosis, hemosiderin may be found in tubular epithelial cells. Renal siderosis has been documented in patients with heart valve prostheses (12) (as in the current case). Studies show its association with prolonged intravascular hemolysis (13). Acute renal failure is more frequent in patients with more pronounced iron deposits (14).

The entire mechanism of iron overload associated renal injury has yet to be elucidated. In part, production of reactive oxygen species is involved. However studies from fresh proximal tubule segments have suggested that iron cytotoxicity may not be linked owing to free radical injury because of the protective effect of scavenger systems for free radicals present within these cell types. Therefore, in proximal tubules, iron may cause cytotoxicity by mechanisms independent of (·OH) (15).

In the remnant kidney models, iron enters the tubular lysosomes across the brush-border membrane by endocytosis. Likewise, hemosiderin accumulates within proximal tubular lysosomes in several models of renal disease. Studies have shown tubular damage potentiates iron accumulation (13). Thus, cellular accumulation of iron has been implicated in the renal of rhabdomyolysis, ischemic renal disease and glomerulonephritis (16,17).

Iron may contribute to the enhancement of cyclosporine-induced, gentamycin-induced and cisplatin-induced nephrotoxicity. A number of studies have shown an increase in free radical production during storage of organs (18). It is possible that iron released during cold ischemia may play a part in free radical production. Use of the iron chelator DFO in cold storage solution has been shown to markedly reduce renal tubular injury. Administration of iron chelators has been shown to improve subsequent organ function (19).

Considering the myriad ways in which iron can damage the kidney and reduce its function, it was interesting to note how an iron-overloaded kidney would perform post-transplant. Given the limitations in terms of patient number (only one) and period of follow up (2 years) no significant conclusions can be drawn from our case report. However, in this particular case, the iron overload of the kidney did not seem to have an immediate or long-term (2 years post-transplant) adverse effect. In the discussion above, a role for iron in ischemic injury was noted, however, no augmented sensitivity to ischemia was noted in our case. The one episode of acute rejection was transient and well controlled with treatment. In all probability, it was related to factors other than the renal siderosis. Renal function seemed adequate immediately post-transplant and after 2 years. The slowly increasing creatinine is attributed to chronic allograft nephropathy and cannot be directly correlated with iron. Over the 2 years, a quantitative decrease was noted in tubular epithelial iron load, which was 4+ in the pretransplant biopsy, 1+ in the 1-year post-transplant biopsy and patchy at 2 years with an associated modest increase in interstitial hemosiderin-containing macrophages. The mechanism of this clearance may be exocytosis (14) or some unknown pathway. The patient was not treated with iron chelator therapy.

There is a need to report cases in which donor kidneys with suboptimal parameters have been utilized for transplantation. Shared experience will facilitate more educated evaluation of the marginal donor pool. However generalized conclusions cannot be drawn from a single case report.