Calcium Oxalate Deposition in Renal Allografts: Morphologic Spectrum and Clinical Implications


*Corresponding author: Luan D. Truong,


Many aspects of calcium oxalate (CaOx) deposition in renal transplant biopsies are not known. Review of all renal transplant biopsies performed in a 7-year period showed that CaOx deposition could be classified into three groups. Group I: Seven biopsies within a month post-transplant displayed rare CaOx foci against a background of acute tubular necrosis or acute cell-mediated rejection. At follow-up, five grafts functioned well and two failed due to chronic allograft nephropathy. CaOx in this context was an incidental finding secondary to a sudden excretion of an end-stage renal disease-induced increased body burden of CaOx. Group II: Two biopsies performed 2 and 10 months post-transplant showed rare CaOx foci against a background of chronic allograft nephropathy, leading to graft loss. CaOx in this context reflected nonspecific parenchymal deposition due to chronic renal failure regardless of causes. Group III: One biopsy with recurrent PH1 characterized by marked CaOx deposition associated with severe tubulointerstitial injury and graft loss 6 months post-transplant. There were two previously reported cases in which CaOx deposition in the renal allografts was due the antihypertensive drug naftidrofuryl oxalate or increased intestinal absorption of CaOx. CaOx deposition in renal allografts can be classified in different categories with distinctive morphologic features and clinical implications.


Deposition of calcium oxalate (CaOx) is rarely identified in native kidneys and its clinicopathologic features are well defined. Deposition of CaOx is probably more often seen in renal allografts as anecdotally mentioned in standard textbooks or monographs (1). Careful literature review shows, however, only a few pertinent reports. Olsen and co-workers noted CaOx deposition in 10 out of 13 (77%) renal transplant (Tx) biopsies with acute tubular necrosis (ATN) (2). Memeo et al. reported CaOx deposition in 35/40 (87%) allograft nephrectomy specimens with diverse causes of graft failure (3). de Strihou's group reported two renal allografts with CaOx deposition and reversible acute renal failure secondary to chronic pancreatitis-induced increased intestinal absorption of CaOx and an overdose of the antihypertensive drug naftidrofuryl oxalate, respectively (4,5). A systematic study focusing on the significance of CaOx deposition in renal allografts is, however, not available.

Materials and Methods

All renal Tx biopsies performed at the Methodist Hospital/Baylor College of Medicine, Houston, Texas, in a 7-year period between 1995 and 2002 were reviewed to identify those with CaOx deposition. A separate case of recurrent primary hyperoxaluria, Type 1 (PH1) from Texas Children's Hospital was also included. The renal Tx biopsies were subjected to light microscopy (LM) using hematoxylin and eosin (H&E), periodic acid-Schiff (PAS), Mason's trichrome (trichome), and Gomori's methenamine silver (silver) stains. Selected biopsies were submitted to von Kossa's, Alizarin red, and Pizzolato's stains, the last of which is known to be specific for CaOx (6). The biopsies performed 2 months post-Tx or later were also submitted to immunofluorescent (IF) study for IgG, IgM, IgA, C3, C4, kappa and lambda light chains, with or without electron microscopic (EM) study. CaOx deposition was identified under polarized light and its density was expressed as foci of CaOx per 20× field of a Nikon microscope Model M048 (Nikon, Houston, TX, USA). The patients' medical records were reviewed with special attention to the conditions, which has been known to be associated with increased intestinal absorption or synthesis of CaOx. The renal biopsy findings were tabulated and correlated with the clinical findings at time of biopsy and during follow-up.


Thirteen out of 315 (4%) renal Tx biopsies from nine patients showed CaOx deposition. The clinicopathologic features of these cases and of the case with recurrent PH1 are summarized in Table 1. Exogenous sources of CaOx or conditions that promote its intestinal absorption were not identified in any patients. Three groups of patients were identified.

Table 1.  Calcium oxalate deposition in renal allografts. Clinicopathologic features
Cause of ESRDInitial BiopsyRepeated BiopsyFollow-up






  1. aThis patient received both liver and kidnet transplants.

Group I
 Diabetic6 days4.2None0.4Acute cellNot done 4 monthsFunctioning
   nephropathy  and antibody- 
 Hypertensive  mediated 
   nephropathy  rejection 
 Diabetic5 days6.8None0.75Acute cell-16 days0.7Acute cell-3 monthsFunctioning
   nephropathy  mediated  mediated 
 Hypertensive  rejection  rejection 
 FSGS4 days8.233Acute cell-25 days2Acute cell-1 yearFailed
  mediated  mediated 
  rejection  rejection 
 Hypertensine10 days6.2None1AcuteNot done 5 yearsFunctioning
   nephropathy  tubular 
 'Glomerulo5 days7None3.8AcuteFour0Chronic1 yearFailed
   nephritis'  tubular repeated  allograft 
  necrosis biopsies  nephropathy 
  1 month 
 Anti-GBM9 days5None0.8Acute20 days0.6Acute16 monthsFunctioning
   disease  tubular  tubular 
  necrosis  necrosis 
 Primary8 days3.6None0.8AcuteNot done 18 monthsFunctioning
   hyperoxaluria,  tubular  
   Type 1a  necrosis 
Group II
 Hypertensine2 months161Chronic8 months0.75Chronic4 yearsFailed
   nephropathy  allograft  allograft 
  nephropathy  nephropathy 
 Diabetic10 months3None0.8ChronicNot done 2 yearsFailed
   nephropathy  allograft  
Group III
 Primary4 months6.5Anuria28.5Recurrent6 months15.6Recurrent15 monthsFailed
   hyperoxaluria,  primary  primary 
   Type 1  oxalosis  oxalosis 

Group I

This group included seven patients with ages ranging from 16 to 52 years, each of whom received a cadaveric renal transplant. PH1 was the cause of end-stage renal disease (ESRD) in one of these patients, who also received a cadaveric liver transplant. The pre-Tx plasma levels of Ox of this patient was 99 μmol/L (<60 μmol/L for dialysis-dependent patients in general), and plasma glycolate, 421 μmol/L (normal 9–42 μmol/L). Tx biopsies were performed 4–10 days post-Tx for delayed graft function, at which time the serum creatinine ranged from 3.6 to 8.2 mg/dL. There was no urine protein excretion in six patients, but protein excretion of 3 g/day was noted in one with recurrent focal segmental glomerulosclerosis. The Tx biopsies showed 0.4–3.8 foci of CaOx per 20× microscopic field, which appeared as isolated or aggregated polygonal crystals noted mostly in proximal tubules and rarely in collecting ducts, but not elsewhere in the kidney. The crystals were intracytoplasmic or located within tubular lumen and were not associated with any significant changes of the adjacent tubular cells (Figure 1A–C). The crystals were colorless, but displayed multicolored birefringence under polarized light in H&E sections, negative for the von Kossa and Alizarin red stains, positive for the Pizzolato's stain, but were not seen in the PAS-, trichome-, or silver-stained sections. The features of CaOx deposition in the Tx biopsy from the patient with PH1 were similar to the other Tx biopsies. The CaOx deposition was found against the background of ATN (four biopsies, including the one in the patient with PH1) or acute cell-mediated rejection (three biopsies). Although repeated renal Tx biopsy was not done and no data on urinary oxalate level were available post-Tx, we believe that the CaOx deposition in this patient represents an example of Group I because there was only focal CaOx deposition (0.8 foci/high power field) against a background of acute tubular necrosis, without advanced chronic tubulointerstitial injury. Furthermore, the patient regained normal function shortly after the biopsy and the graft functioned well (serum creatinine 1.4 mg/dL) 18 months post-Tx. In fact, it can be assumed that Ox metabolism was normalized by the liver transplantation. In contrast, recurrent oxalosis, as exemplified by the single patient in Group III (see below), is characterized by widespread CaOx deposition associated with severe and chronic injury of the renal transplant and this almost always leads to graft loss.

Figure 1.

Early post-transplant calcium oxalate (Group I). (A) Rare calcium oxalate crystals in the lumen of some proximal tubular cross section (arrows). There are no significant tubulointerstitial changes in this field. (Hematoxylin & eosin, ×800). (B) The same field viewed under polarized light illustrates the characteristic features of calcium oxalate crystals. (C) Calcium oxalate crystals within a proximal tubular cell, without tubulointerstitial injury (Hematoxylin & eosin, ×800).

Repeated Tx biopsies were performed in four patients within a month post-Tx. Four repeated biopsies performed in one patient did not show CaOx but revealed progressive chronic allograft nephropathy. One repeated biopsy was performed in each of the three other patients, and they showed less pronounced CaOx deposition against the same background changes as seen in the original biopsies. At follow-up of up to 5 years, two grafts failed due to chronic allograft nephropathy and post-Tx NS, respectively, and the other five remained functional, including the one in the patient with PH1.

Group II

This group included two patients, one of whom received a cadaveric renal transplant at the age of 72 years and the other, a living-related renal transplant at the age of 35 years. Tx biopsies were performed 2 and 10 months post-Tx for nephrotic syndrome and persistently elevated serum creatinine (3 mg/dL), respectively. The CaOx deposition was similar to that of the biopsies in Group I, but it was found against the background of chronic allograft nephropathy characterized by chronic tubulointerstial injury, chronic allograft glomerulopathy, and vascular intimal fibrosis (Figure 2).

Figure 2.

Calcium oxalate associated with chronic allograft nephropathy (Group II). Calcium oxalate crystals in a mildly dilated proximal tubular lumen (lower left). There are tubular atrophy, interstitial fibrosis, and minimal interstitial inflammation (Hematoxylin & eosin, ×1600).

Repeated biopsy in one patient showed persistent CaOx deposition and more severe chronic allograft nephropathy. The grafts failed in both patients at 4 and 2 years post-Tx, respectively.

Group III

This group included one patient from Mexico with a history of growth retardation. At the age of 6 years, she developed 'acute renal failure' after a short period of nausea, vomiting and diarrhea. A kidney biopsy was not performed. She received a living-related renal Tx after 3 months on dialysis and the renal function returned to normal within a week. Starting at 3 months post-Tx, the serum creatinine began to rise and reached 6.5 mg/dL at 4 months post-Tx. The Tx biopsy showed severe and diffuse CaOx deposition in interstitium and cells and lumens of proximal tubules associated with cytoplasmic vacuolization, necrosis, apoptosis, or bare tubular basement membrane (Figure 3A and B). There was severe interstitial fibrosis but no rejection. The patient was transferred to Texas Children's Hospital, where a repeated Tx biopsy showed the same changes as the original one. CaOx deposition was not seen in other organs by various imaging studies. Subsequent investigation including the serum levels of oxalate (99 μmol/L, <60 μmol/L for dialysis-dependent patients in general), glycolate (428 μmol/L, normal 9–42 μmol/L), the level of alanine/glyoxylate aminotransferase (none detected) in liver, and genetic studies confirmed the diagnosis of PH1. Graft failure due to recurrent PH1 was diagnosed and the patient was put on peritoneal dialysis.

Figure 3.

Recurrent oxalosis (Group III). (A) Numerous colorless and refractive calcium oxalate crystals within focally dilated tubular lumens. There is severe tubular atrophy and interstitial fibrosis (Hematoxylin & eosin, ×800). (B) The same field viewed under polarized light.


The current study shows that CaOx crystals in renal allografts are morphologically distinct and similar to those in native kidneys, i.e. colorless but refractive polygonal structures with multicolored birefringence under polarized light (1). These features enable not only easy identification of these crystals but also accurate recognition of their chemical nature. The special stains, i.e. von Kossa, Alizarin red and Pizzolato, performed retrospectively in this study to confirm the chemical nature of the CaOx crystals, are indeed not needed routinely. These crystals, however, are not observed in PAS-, trichome-, or silver-stained sections, even in cases with massive deposition, indicating that CaOx is dissolved during these procedures. CaOx deposition in renal allografts, identified in about 4% of unselected renal Tx biopsies in this study, is rather infrequent. Although higher incidences were reported in studies by Olsen et al. (77%) and Memeo et al. (87%), the latter included only Tx biopsies with ATN and only allograft nephrectomy specimens were studied in the latter (2,3). The current study and the related literature suggest that CaOx deposition in renal allografts may develop in four different clinical contexts, each of which is characterized by distinct morphology and clinical implications (Table 2).

Table 2.  Causes of calcium oxalate (CaOx) deposition in renal allografts
  1. Tx: transplant.

Early post-Tx accumulation of CaOx
 Immediate post-Tx period
 Usually few foci of CaOx
 Background of acute rejection or acute tubular necrosis
 Renal function back to normal
Chronic renal failure
 Months after Tx
 Usually few foci of CaOx
 Background of chronic allograft nephropathy
 Outcome depending on the background renal injury
Recurrent primary hyperoxaluria
 Variable time after Tx, usually within weeks
 Widespread renal deposition of CaOx
 Associated with chronic tubulointerstitial injury
 Associated with graft loss
Secondary hyperoxaluria
 Due to increased intestinal absorption of Ox or Ox-containing
   drug (naftidrofuryl oxalate)
 Pronounced CaOx deposition
 Multifocal tubular cell necrosis
 Reversible acute renal failure

As demonstrated in Group I, CaOx deposition may be found in renal Tx biopsies shortly after Tx against the background of ATN or acute rejection but not acute or chronic tubular cell injury. The deposition is usually scanty and almost exclusively limited to proximal tubules. This is probably the most frequent type of CaOx deposition in renal allografts. Ox is normally filtered through the glomerular capillaries and undergoes bi-directional transport through the proximal tubules (7). A small amount of oxalate may be normally secreted by the enteric route at least in rat, and this excretion may be significantly enhanced in case of renal failure (7). Because kidney is the major organ through which Ox is eliminated and dialysis can only remove a fraction of the daily Ox intake, the serum level of Ox in ESRD patients is progressively increased (8–11). Although this may be associated with increased body burden of Ox (8–11), some studies suggest that these patients may achieve Ox balance, with elevated plasma Ox levels, but without significant tissue accumulation of Ox (12,13). After successful renal Tx, a large amount of Ox is excreted into urine and the serum Ox level returned to normal between 3 d and 3 weeks post-Tx in all patients whose original renal diseases are not primary hyperoxaluria (10,11). These considerations suggest that increased tubular load of Ox is routinely expected in the immediate post-Tx period, and Ox may precipitate in tubular cell or tubular lumen. Because only a small percentage of unselected renal Tx biopsies (around 4% in this study) showed CaOx, additional pathogenetic factors may be involved. ATN may facilitate CaOx deposition, as suggested by the presence of CaOx in 10/13 Tx biopsies with ATN reported by Olsen et al. (2), in four out of five grafts with 'ischemic necrosis' reported by Memeo et al. (3), and in five out of 10 (50%) Tx biopsies in this study. Although the reverse sequence, i.e. CaOx deposition may cause ATN, cannot be ruled out, this is highly unlikely considering the scant CaOx deposition in this context, the lack of necrosis of the tubular cells in contact with CaOx, and the presence in the current study of several Tx biopsies with the type of CaOx deposition similar to that seen in biopsies with ATN but showing acute cell-mediated rejection, rather than ATN. Uremia was present in 27 out of 29 patients whose kidneys at autopsy displayed CaOx deposition, but pathologic changes were noted in only 50% of these kidneys (14). Anuria was present in all seven patients in the Group I of this study. These observations suggest that lack of tubular flow may facilitate CaOx deposition. CaOx may have a direct cytotoxic effect on renal tubular epithelial cells and this may be a factor that can promote further CaOx deposition. Although pathogenetically unsettled, CaOx deposition in this group probably represents an incidental finding of no clinical significance as the poor graft function in each patient was related to ATN or acute cell-mediated rejection and resolved after appropriate therapy.

CaOx can deposit in native kidneys in patients with chronic renal failure regardless of causes (8,14). This can also happen in renal allografts, as shown by the two cases in Group II. Although the morphology of the CaOx per se in these cases is similar to those in Group I, the kidneys in these cases typically display chronic allograft nephropathy characterized by tubular atrophy, interstitial fibrosis, interstitial inflammation associated with irreversible loss of renal function, corresponding to the timing of biopsies usually months or years post-Tx. In this aspect, Memeo et al. reported CaOx deposition in 35 out of 40 (87%) renal allografts removed 2–11 years post-Tx (3). In the same study, CaOx deposition was associated with acute ischemic necrosis in four Tx nephrectomy specimens. Although the mechanism of this association was not discussed, it is possible that renal CaOx deposition in these cases may be due to chronic allograft nephropathy and this developed even before ischemic necrosis. Acute ischemic necrosis was only rarely identified in renal Tx biopsy in our study and CaOx was not seen in any of these biopsies.

CaOx in renal allografts may signify recurrent PH1 (Group III). The recurrence usually develops shortly after Tx with massive CaOx deposition associated with severe acute and chronic renal tissue injury resulting in graft loss (15–19). The high recurrence rate is probably related to a heavy pre-Tx body burden of CaOx and a high plasma level of Ox in PH1 patients, which far exceed those in other ESRD patients (11). Plasma oxalate remains elevated beyond 6 months even with successful renal transplantation if oxalate production is not normalized by hepatic transplantation or, in rare cases, thanks to a full response to pyridoxine (11), whereas plasma oxalate levels returned to normal in others within days (10). In contrast to those in Group I or II, CaOx deposition is most likely the cause of the uniformly observed severe renal tissue injury in recurrent PH1. CaOx crystals may cause damage to tubular or interstitial cells through physical contact or through other mechanisms including release of tubular basement antigen or inflammatory cell/reactive oxygen species-mediated endothelial cell injury, as suggested by in vitro studies (17,20,21). The current case also shows that CaOx deposition in renal Tx may be the first clue for PH1, as recently reported (22). Some PH1 patients may present with ESRD, for which renal Tx is offered without biopsy of the native kidney and PH1 was first suggested by its recurrence in the renal allograft (17,22). It should be emphasized that CaOx in renal allografts of those with PH1 does not necessarily indicate recurrent disease but may represent an incidental finding encountered in the context of those in Group I of this study. This is exemplified by one of our patients and was previously reported (16,18,23). The difference in the post-Tx courses of the two PH1 patients in our study may be related to the fact that in the patient with recurrent disease, the diagnosis of PH1 was not made before transplantation and appropriate pre- and post-Tx care including pyridoxine and intense dialysis to decrease the body burden of CaOx was not attempted. In contrast, the diagnosis of PH1 was definitively made 21 months prior to the renal transplant in the patient with a good outcome. She was treated with pyridoxine, was well prepared for renal transplantation, and also received a liver transplant. The liver transplant provided alanine/glyoxylate aminotransferase activity, which may help normalize Ox metabolism and prevent recurrent oxalosis.

CaOx deposition in native kidneys may be secondary to increased dietary ingestion of CaOx-containing food or medication or poisoning by Ox precursors (1). Intestinal absorption of CaOx occurs mostly in large bowel and is facilitated by fatty acid and bile salts. Any condition associated with fat malabsorption such as Crohn's disease, chronic pancreatitis, or small intestinal bypass surgery may cause increased colonic content of fat and promote Ox absorption potentially leading to renal oxalosis (1). Oxalobacter formigenes, a saprophytic bacterium in colon, was recently found to degrade ingested Ox salts and its loss or decrease may be a factor in increased intestinal absorption of Ox leading to hyperoxalemia (24). These conditions were not observed in any of the patients in the current study, but they may rarely be the causes of CaOx deposition in renal allografts, as evidenced by the reports of extensive CaOx deposition associated with acute graft failure due to chronic pancreatitis-induced steatorrhea or overdose of naftidrofuryl oxalate (Praxilene), an antihypertensive medication with Ox accounting for 19% of total weight (4,5). Pre- or post-Tx urine or serum Ox levels were not available in any patients in this study, except for the two with primary oxalosis. Secondary hyperparathyroidism, indicated by elevated serum parathormone levels, was seen in two patients.

In conclusion, CaOx deposition in renal allografts is rather unusual and can be classified in different categories with distinctive morphologic features and clinical implications.