Primary hyperoxaluria diagnosed after kidney transplantation failure: lesson from 3 case reports and literature review

A 27-year-old male hypertensive patient was referred to our department on Nov 15, 2017, after right nephrectomy as well as left minimally invasive percutaneous nephrolithotomy (mini-PCNL). With a history of symptomatic kidney stones for more than 10 years and elevated SCr level for more than 3 years, accompanied with hypertension (peak 170/98 mmHg), the patient was scheduled to receive the renal transplantation.

The patient was rehospitalized on Apr 28, 2018, with SCr 1487 umol/L and BUN 33.47 mmol/L (shown in Additional file 1: Figure S1). He underwent renal transplantation that night, with a deceased donor, which was performed with Zero-Hour Implantation biopsy (ZHIB, as part of the routine renal transplant procedure, shown in Fig. 1a, 200X HE). The patient received standard immunosuppression with mycophenolate mofetil (MMF), tacrolimus (Tac) and methylprednisolone (Methylpred) besides hemodialysis (HD), as well as hypertension treatment. Additionally, he received the follow-up assessments including routine blood tests, blood biochemical analysis and therapeutic drug monitoring regularly (Additional file 1: Figure S1). However, it was less likely to have improvements in the renal graft function.

Due to the delayed graft function (DGF, SCr 585 umol/L and BUN 30.07 mmol/L), the patient received percutaneous needle core biopsy of renal graft on post-operative (post-op) day 46, guided by ultrasonography (USG) (Fig. 1b). Renal graft biopsy revealed acute T cell-mediated rejection (TCMR, 2015 Banff 1A) and extensive tubular damage, with the presence of the emerging deposition of CaOx crystals in the allograft (Fig. 1c, 200X HE and polarized light). Compared with ZHIB, recurrence of CaOx nephropathy was confirmed in the allograft kidney. Molecular genetic testing of the patient was carried out to identify the pathogenic variants (PV) in AGXT and GRHPR, in whom a homozygous genotype for three missense mutations in the GRHPR gene was found: first, a C to T transversion (c.295C > T) in exon 4 resulting in p.(Arg99*), nonsense PV; second, a G to A transversion (c.512G > A) in exon 6 resulting in p.(Arg171His), missense variant of uncertain significance (VUS); third, a G to A transversion (c.211G > A) in exon 2 resulting in p.(Ala71Thr), missense VUS (shown in Table 1 and Fig. 1d). Based on the previous findings a diagnosis of PH2 was made.

We further analyzed the DNA of the patient’s family. Sequencing analysis of the GRHPR gene showed that the PV (c.295C > T) was also found in the patient’s mother, who presented asymptomatic kidney stones. Unfortunately, the other two VUS were detected both in the patient’s father and son (shown in Table 1 and Fig. 1d).

The patient was treated with Pyridoxine (PN, Vitamin B6) and temporarily intensive HD besides the basic immunosuppression to suppress oxalate overproduction. Furthermore, for the failure of kidney-alone transplantation (KAT), we recommended the treatment scheme with the combined Liver-Kidney Transplantation (LKT) before the development of systemic oxalosis but was refused by the patient. The patient currently reentered to the maintenance HD in the clinic and looked forward to a chance of LKT in the future.

A 26-year-old male non-hypertensive patient was hospitalized on Aug 11, 2016, with an 8-year history of the elevated SCr, which included a 7-year history of maintenance HD. The next day, attributed to the preoperative SCr 893 umol/L and BUN 27.32 mmol/L, shown in Additional file 2: Figure S2), he was transplanted with a deceased kidney donor performed with routine ZHIB (Fig. 2a, 200X HE). The patient received standard triple immunosuppression following transplantation as well as the follow-up assessments regularly. Similarly, even though we substituted Cyclosporine A (CsA) for Tac, renal graft gradually developed DGF (SCr 534 umol/L and BUN 30.06 mmol/L, Additional file 2: Figure S2), and USG-guided renal biopsy was employed on post-op day 38 (Fig. 2b). Deposition of diffuse CaOx crystals as well as acute TCMR (2015 Banff 2A) was detected in renal graft biopsy (Fig. 2c, 200X HE and polarized light), whereas there were no oxalate crystals in the ZHIB. Molecular genetic testing identified two mutations in the AGXT gene: first, exon 1: c.33dupC (p. Lys12fs), frameshift PV; second, an A to T transversion (c.215A > T) in exon 2 resulting in p. Asn72Ile, missense VUS. Meanwhile, it was noteworthy that one mutation in the MUT gene (Exon11: c.1897G > C (p. Val633Leu), missense VUS) was detected in the patient. Thus, the patient was diagnosed with PH1 and treated with PN (400 mg, iv, QD) and temporary intensive HD.

Owing to the anemia (hemoglobin level, HGB, 57–74 g/L; shown in Additional file 2: Figure S2), bone marrow biopsy was conducted on post-op day 70, which showed intertrabecular spaces occupied by abundant CaOx crystals (Fig. 2d, 200X HE, 400X HE and polarized light). Apparently, the patient was diagnosed as systemic oxalosis of PH1 with CaOx crystals involving both the allograft kidney and bone marrow, the latter is the most crippling site of CaOx deposition. He was treated with concentrated red blood cells (CRBC) transfusion and recombinant human erythropoietin (rhEPO) to correct the anemia. Moreover, as renal graft loss, he returned to the maintenance HD and received the optimal immunosuppression. Up till now, the patient was investigated for the overall decline in health following allograft failure.

A 34-year-old male hypertensive patient was admitted to hospital on Oct 16, 2015, for the first time because of the elevated SCr level for more than 12 months. Presented with SCr 1222 umol/L and BUN 24.33 mmol/L (Additional file 3: Figure S3) as well as hypertension peaked at 180/100 mmHg, the patient waited for the renal transplantation.

The patient was readmitted to hospital on Jan 5, 2016. He received a kidney allograft on the next day with a deceased donor performed with routine ZHIB (Fig. 3a), followed by post-op standard triple immunosuppression besides HD. Furthermore, the follow-up assessments were executed nearly once a day (Additional file 3: Figure S3). However, the course was unfavorable with DGF emerging. USG-guided renal graft biopsy (Fig. 3b) was performed on post-op day 75, which documented acute TCMR (2015 Banff 2A) and extensive deposits of CaOx crystals in the interstitial tubule (Fig. 3c, 200X HE and polarized light). In view of the fact that no oxalate crystals deposited in the ZHIB, as well as the history of kidney stones in the recipient, recurrence of CaOx nephropathy following kidney transplantation was confirmed, which led to the diagnosis of PH. However, the diagnosis of PH must depend on the genetic testing. Unfortunately, molecular genetic testing of the patient was not carried out to identify the PV in AGXT, GRHPR or HOGA1 for some reasons.

Although the renal function of the patient was slowly repaired (SCr 260 umol/L; BUN 14 mmol/L), the treatment by HD was ineffective in treating excess oxalate besides the drug immunosuppression. Accompanied by the fever of 39.8 °C (Body temperature shown in Additional file 3: Figure S3) and intermittent cough, Pneumocystis jirovecii pneumonia (PJP) was confirmed in the patient on May 25 by fiberoptic bronchoscopic (FOB) biopsy (Fig. 3d, 600X HE and Methylamine silver) as well as subsequent Chest CT examination (Fig. 3e). The patient was initially treated with empirical anti-infection therapy (Micafungin) as well as γ-globulin. Meanwhile, standard triple immunosuppression was replaced with the pulse intravenous Methylpred. Even though the clinicians enhanced the anti-infection therapy with administration of trimethoprim-sulfamethoxazole (TMP/SMX) and voriconazole (VOR) orally, as well as meropenem (MEM) was used in the final stage, the patient died of severe pneumonia caused by P. jirovecii on Jun 28, 2016.