• 1.

    Alshaikh AE, Hassan HA. Gut-kidney axis in oxalate homeostasis. Curr Opin Nephrol Hypertens 2021; 30:264274. doi: 10.1097/MNH.0000000000000690

    • Search Google Scholar
    • Export Citation
  • 2.

    Perinpam M, et al. Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease. Clin Biochem 2017; 50:10141019. doi: 10.1016/j.clinbiochem.2017.07.017

    • Search Google Scholar
    • Export Citation
  • 3.

    Nasr SH, et al. Oxalate nephropathy complicating Roux-en-Y gastric bypass: An underrecognized cause of irreversible renal failure. Clin J Am Soc Nephrol 2008; 3:16761683. doi: 10.2215/CJN.02940608

    • Search Google Scholar
    • Export Citation
  • 4.

    Roodnat JI, et al. A successful approach to kidney transplantation in patients with enteric (secondary) hyperoxaluria. Transplant Direct 2017; 3:e331. doi: 10.1097/TXD.0000000000000748

    • Search Google Scholar
    • Export Citation
  • 5.

    Cornell LD, et al. Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transplant 2022; 22:8595. doi: 10.1111/ajt.16732

    • Search Google Scholar
    • Export Citation
  • 6.

    Garrelfs SF, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 2021; 384:12161226. doi: 10.1056/NEJMoa2021712

    • Search Google Scholar
    • Export Citation
  • 7.

    Palsson R, et al. The association of calcium oxalate deposition in kidney allografts with graft and patient survival. Nephrol Dial Transplant 2021; 36:747. doi: 10.1093/ndt/gfy364 [Erratum to Nephrol Dial Transplant 2020; 35:888–894. doi: 10.1093/ndt/gfy271].

    • Search Google Scholar
    • Export Citation
  • 8.

    Truong LD, et al. Calcium oxalate deposition in renal allografts: Morphologic spectrum and clinical implications. Am J Transplant 2004; 4:13381344. doi: 10.1111/j.1600-6143.2004.00511.x

    • Search Google Scholar
    • Export Citation
  • 9.

    Pinheiro HS, et al. Early presence of calcium oxalate deposition in kidney graft biopsies is associated with poor long-term graft survival. Am J Transplant 2005; 5:323329. doi: 10.1111/j.1600-6143.2004.00684.x

    • Search Google Scholar
    • Export Citation
  • 10.

    Bagnasco SM, et al. Oxalate deposits in biopsies from native and transplanted kidneys, and impact on graft function. Nephrol Dial Transplant 2009; 24:13191325. doi: 10.1093/ndt/gfn697

    • Search Google Scholar
    • Export Citation
  • 11.

    Witting C, et al. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol 2021; 16:487495. doi: 10.2215/CJN.08000520

Oxalate Nephropathy in Kidney Transplantation

  • 1 Sambhavi Krishnamoorthy, MD, is with the Division of Nephrology, University of Chicago Biological Sciences Division, Chicago, IL.
Full access
Introduction

Oxalate or oxalic acid is a dicarboxylic acid formed in the human body from exogenous dietary sources and endogenous metabolism of ascorbic acid and some amino acids. It is essentially a terminal metabolic product that is produced by the liver, absorbed by the intestine from dietary sources, and freely filtered by the kidneys (Figure 1) (1). There is no human enzyme that can degrade it further.

Regional disparity in deceased donor kidney transplant rates

Hepatic metabolism and dietary oxalate absorption generate plasma oxalate, which is then primarily excreted by kidneys into urine.

Introduction

Oxalate or oxalic acid is a dicarboxylic acid formed in the human body from exogenous dietary sources and endogenous metabolism of ascorbic acid and some amino acids. It is essentially a terminal metabolic product that is produced by the liver, absorbed by the intestine from dietary sources, and freely filtered by the kidneys (Figure 1) (1). There is no human enzyme that can degrade it further.

Figure 1
Figure 1

Regional disparity in deceased donor kidney transplant rates

Citation: Kidney News 14, 7

Hepatic metabolism and dietary oxalate absorption generate plasma oxalate, which is then primarily excreted by kidneys into urine. Figure 1 and part of legend are reprinted from Witting et al. (11).

Hyperoxaluria is divided into two types: primary hyperoxaluria (PH), which results from increased production in the liver, and secondary or enteric hyperoxaluria, due to increased absorption of oxalate in the gut, increased dietary consumption, or decreased metabolism by gut bacteria (Table 1). Individuals with PH have higher oxalate levels for any given glomerular filtration rate compared with enteric hyperoxaluria and stone formers. Similarly, enteric hyperoxaluria also has significantly higher plasma oxalate levels compared with urinary stone formers (2). End stage kidney disease (ESKD), by itself, leads to higher-than-normal oxalate levels, the degree of which depends on frequency and intensity of kidney replacement therapy. Following kidney transplantation, the allograft is exposed to higher plasma oxalate levels, leading to a risk of deposition of calcium oxalate with variable adverse outcomes depending on the clinical scenario. Calcium oxalate crystals in the kidney allograft are observed as transparent crystals, best seen under polarized light (Figure 2) (3).

Table 1

Causes of secondary hyperoxaluria

Table 1
Figure 2
Figure 2

Pathologic findings in oxalate nephropathy

Citation: Kidney News 14, 7

(A) A low-power view shows diffuse tubular degenerative changes with numerous intracellular and intraluminal tubular calcium oxalate deposits. A normal-appearing glomerulus also is present (hematoxylin and eosin [H&E]). (B) The same field as (A) is shown under polarized light. The calcium oxalate crystals are more easily identified (H&E). (C) At high magnification, the calcium oxalate deposits form intraluminal translucent crystals (H&E). (D) In this field, the calcium oxalate crystals are smaller and lie within the cytoplasm of the tubular epithelium. Tubules exhibit prominent degenerative changes, including luminal ectasia, cytoplasmic simplification, and loss of brush border (H&E). Original magnifications, ×40 (A and B); ×400 (C and D) (3).

Case 1

The patient is a 45-year-old female with a history of simultaneous liver-kidney transplant due to alcoholic cirrhosis and hepatorenal syndrome. She underwent gastric bypass surgery 6 years before her transplants. After 1 year of transplantation, she presents with malabsorptive diarrhea and acute kidney injury. An allograft kidney biopsy shows oxalate nephropathy with a serum oxalate level of 77 μmol/L, and she remains dialysis dependent after 4 weeks.

Multiple cases of allograft oxalate nephropathy have been reported in patients with enteric hyperoxaluria. As a part of pre-transplant evaluation, it is important to identify patients with cystic fibrosis, pancreatic insufficiency, bariatric surgery, inflammatory bowel disease, short gut syndrome, or celiac disease who are at risk of fat malabsorption, which leads to increased oxalate absorption. Pre-transplant oxalate levels can help guide changes in diet and intensity of dialysis, leading to a decrease in systemic oxalate load (4). Modification of posttransplant care focused on decreasing the supersaturation of calcium oxalate in the urine, decreasing dietary oxalate, use of calcium-based binders, and intensive dialysis in the setting of delayed graft function (DGF) can lead to successful outcomes (4).

Case 2

The patient is a 39-year-old female with a history of ESKD of unknown etiology. At the age of 2, she developed urinary symptoms, and between the ages of 2 and 5, she had multiple kidney stones. Genetic workup confirms PH type 1. She is approved for simultaneous liver-kidney transplantation. Her preoperative oxalate level is 102 μmol/L.

PH is a rare autosomal-recessive disorder that results from one out of three genetic defects in the liver metabolism of glyoxylate or hydroxyproline. Individuals with PH type 1 and type 2 are at a higher risk of developing chronic kidney disease, ESKD, and systemic oxalosis due to higher plasma oxalate levels, whereas PH type 3 causes a milder dysfunction. It is important to screen patients with a childhood history of nephrocalcinosis/nephrolithiasis for these genetic mutations before transplantation. A kidney-alone transplant has a high risk of recurrence of oxalate nephropathy, leading to allograft failure due to the continued overproduction of oxalate by the liver. Only a subset of patients who respond to pyridoxine therapy can undergo successful kidney-alone transplantation. Currently, liver-kidney transplantation is the gold standard of therapy. Even with successful reduction of hepatic oxalate production with transplantation or via use of pyridoxine, recurrent oxalate deposition due to early transient hyperoxaluria from mobilization of systemic stores does occur. Hence, it is important to individualize care posttransplant with intensive dialysis, calcium binders, and volume expansion with monitoring of plasma oxalate levels in these patients for the best long-term outcomes (5). Newly emerging therapies using RNA interference, such as lumasiran, which have shown successful reduction in hyperoxaluria, may eliminate the need for transplantation (6).

Case 3

The patient is a 64-year-old male with a history of ESKD attributed to diabetes mellitus type 2, with recent deceased donor kidney transplantation (DDKT). The patient develops delayed graft function (DGF) without resolution at 4 weeks after DDKT, and allograft is biopsied showing acute tubular injury and calcium oxalate deposition of unclear clinical significance.

Oxalate deposition in kidney allografts with DGF is common, seen in 4%–53% of biopsies, as described in various retrospective studies (710). This effect was particularly seen in patients with longer time on dialysis, higher serum creatinine, and diabetes. The presence of calcium oxalate deposition in allografts is also associated with DGF and worse patient outcomes at 5 years posttransplant. Whether calcium oxalate deposition is causative or a marker of allograft dysfunction remains unclear (7).

References

  • 1.

    Alshaikh AE, Hassan HA. Gut-kidney axis in oxalate homeostasis. Curr Opin Nephrol Hypertens 2021; 30:264274. doi: 10.1097/MNH.0000000000000690

    • Search Google Scholar
    • Export Citation
  • 2.

    Perinpam M, et al. Plasma oxalate in relation to eGFR in patients with primary hyperoxaluria, enteric hyperoxaluria and urinary stone disease. Clin Biochem 2017; 50:10141019. doi: 10.1016/j.clinbiochem.2017.07.017

    • Search Google Scholar
    • Export Citation
  • 3.

    Nasr SH, et al. Oxalate nephropathy complicating Roux-en-Y gastric bypass: An underrecognized cause of irreversible renal failure. Clin J Am Soc Nephrol 2008; 3:16761683. doi: 10.2215/CJN.02940608

    • Search Google Scholar
    • Export Citation
  • 4.

    Roodnat JI, et al. A successful approach to kidney transplantation in patients with enteric (secondary) hyperoxaluria. Transplant Direct 2017; 3:e331. doi: 10.1097/TXD.0000000000000748

    • Search Google Scholar
    • Export Citation
  • 5.

    Cornell LD, et al. Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function. Am J Transplant 2022; 22:8595. doi: 10.1111/ajt.16732

    • Search Google Scholar
    • Export Citation
  • 6.

    Garrelfs SF, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 2021; 384:12161226. doi: 10.1056/NEJMoa2021712

    • Search Google Scholar
    • Export Citation
  • 7.

    Palsson R, et al. The association of calcium oxalate deposition in kidney allografts with graft and patient survival. Nephrol Dial Transplant 2021; 36:747. doi: 10.1093/ndt/gfy364 [Erratum to Nephrol Dial Transplant 2020; 35:888–894. doi: 10.1093/ndt/gfy271].

    • Search Google Scholar
    • Export Citation
  • 8.

    Truong LD, et al. Calcium oxalate deposition in renal allografts: Morphologic spectrum and clinical implications. Am J Transplant 2004; 4:13381344. doi: 10.1111/j.1600-6143.2004.00511.x

    • Search Google Scholar
    • Export Citation
  • 9.

    Pinheiro HS, et al. Early presence of calcium oxalate deposition in kidney graft biopsies is associated with poor long-term graft survival. Am J Transplant 2005; 5:323329. doi: 10.1111/j.1600-6143.2004.00684.x

    • Search Google Scholar
    • Export Citation
  • 10.

    Bagnasco SM, et al. Oxalate deposits in biopsies from native and transplanted kidneys, and impact on graft function. Nephrol Dial Transplant 2009; 24:13191325. doi: 10.1093/ndt/gfn697

    • Search Google Scholar
    • Export Citation
  • 11.

    Witting C, et al. Pathophysiology and treatment of enteric hyperoxaluria. Clin J Am Soc Nephrol 2021; 16:487495. doi: 10.2215/CJN.08000520

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