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American Journal of Kidney Diseases

Improving a Rare Metabolic Disorder Through Kidney Transplantation: A Case Report of a Patient With Lysinuric Protein Intolerance

Open AccessPublished:October 09, 2022DOI:https://doi.org/10.1053/j.ajkd.2022.08.019

      Abstract

      Lysinuric protein intolerance (LPI) is a rare metabolic disorder with reduced renal and intestinal reabsorption of ornithine, lysine and arginine, due to mutations in the SLC7A7 gene encoding the y+LAT1 transporter, leading to urea cycle defects with protein intolerance. Furthermore, chronic kidney disease (CKD) in LPI is common and can progress to end stage kidney disease requiring renal replacement therapy. Kidney transplantation could in theory improve urine levels and consequently plasma levels of these amino acids and therefore improve clinical symptoms as well as protein intolerance in LPI patients. However data on kidney transplantation in LPI patients is limited and up till now no data on clinical and biochemical improvement after kidney transplantation has been reported. In this case report we describe a rare case of kidney transplantation in a LPI patient with significant improvement in protein tolerance, plasma and urine levels of ornithine, lysine and arginine and on LPI symptoms.

      Index words

      Introduction

      Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disease, caused by mutations in the SLC7A7 gene encoding the y+LAT1 transporter [
      • Perheentupa J.
      • Visakorpi J.K.
      Protein intolerance with deficient transport of basic aminoacids. Another inborn error of metabolism.
      ,
      • Simell O.
      • Perheentupa J.
      • Rapola J.
      • Visakorpi J.K.
      • Eskelin L.E.
      Lysinuric protein intolerance.
      ,
      • Torrents D.
      • Mykkanen J.
      • Pineda M.
      • et al.
      Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.
      ]. Impaired absorption in the intestine and decreased reabsorption in the tubules of the kidney of cationic amino acids causes low plasma levels of ornithine, lysine and arginine [4 5]. Symptoms most often present in childhood and mimic primary urea cycle defects consisting of protein intolerance, delayed growth, osteoporosis, hepatosplenomegaly, muscle hypotonia, macrophage activation, pulmonary fibrosis and chronic hemophagocytic lymphohistiocytosis (Box 1) [
      • Rajantie J.
      • Simell O.
      • Perheentupa J.
      • Siimes M.A.
      Changes in peripheral blood cells and serum ferritin in lysinuric protein intolerance.
      ,
      • Ogier de Baulny H.
      • Schiff M.
      • Dionisi-Vici C.
      Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder.
      ,
      • Noguchi A.
      • Takahashi T.
      Overview of symptoms and treatment for lysinuric protein intolerance.
      ]. These symptoms may occur secondary to arginine deficiency, hyperammonemia and/or immune disorders caused by the primary membrane transport defect for dibasic amino acids in the kidneys, intestine and lymphoid cells [
      • Noguchi A.
      • Takahashi T.
      Overview of symptoms and treatment for lysinuric protein intolerance.
      ].
      Main clinical features of Lysinuric Protein Intolerance
      Tabled 1
      First symptoms after weaning from breast milk or formula
      Postprandial hyperammonemia with stupor and/or coma after protein ingestion
      Aversion to protein meals
      Recurrent episodes of vomiting and diarrhea
      Short stature because of malnutrition and failure to thrive
      Recurrent viral infections
      Hepatosplenomegaly
      Muscle hypotonia
      Osteoporosis
      Pulmonary involvement with fibrosis, interstitial pneumonia and pulmonary alveolar proteinosis
      Chronic hemophagocytic lymphohistiocytosis
      Renal involvement, mostly tubular lesions often progressing to CKD
      Renal involvement in LPI is common and can lead to progressive chronic kidney disease (CKD) and end stage kidney disease (ESKD) [

      Tanner LM, Nanto-Salonen K, Niinikoski H, et al. Nephropathy advancing to end-stage renal disease: a novel complication of lysinuric protein intolerance. J Pediatr 2007;150(6):631-634, 34 e1 doi: 10.1016/j.jpeds.2007.01.043 [published Online First: 2007/05/23].

      ]. Findings in renal biopsies of LPI patients are non-specific and can vary from tubulointerstitial involvement to heterogeneous glomerular lesions and even amyloidosis [
      • Esteve E.
      • Krug P.
      • Hummel A.
      • et al.
      Renal involvement in lysinuric protein intolerance: contribution of pathology to assessment of heterogeneity of renal lesions.
      ].
      Because increased urinary excretion of amino acids plays an important role in LPI pathogenesis, a kidney transplant with normal dibasic amino acid transport might be expected to improve the symptoms of LPI. To our knowledge kidney transplantation has been described in five LPI patients, however no data is available on symptoms, protein tolerance or amino acid levels after kidney transplantation [9 11]. Furthermore, no data is available on increasing protein intake after kidney transplantation or on attempts to taper treatment. In this case report we present a remarkable case of LPI with severe renal involvement and describe the course of LPI symptoms, protein tolerance and biochemical parameters after kidney transplantation.

      Case report

      A 37 year-old Caucasian female with a history including high ferritin with a compound heterozygous mutation for hemochromatosis and osteopenia was referred with CKD, proteinuria, tubular dysfunction with a high urinary output of alpha-1-microglobulin and beta-2-microglobulin, and erythrocyturia in 2004. A kidney biopsy at that time did not provide a classifying diagnosis. In 2006 a repeat biopsy was obtained because of progressive loss of kidney function. Light microscopy revealed signs of glomerular infiltration and ischemia with concurrent signs of interstitial infiltration and fibrosis around the affected glomeruli. Erythrocyte casts were found as well as hemosiderin suggesting hemolysis. There were no signs of thrombotic microangiopathy. Immunofluorescence showed deposits of IgG, IgA, C3, kappa, lambda and fibrine, all in low quantities. Electron microscopy revealed podocyte injury and subendothelial as well as mesangial 15 nanometer fibrils. A diagnosis of fibrillary glomerulonephritis was assumed. Due to the advanced stage of CKD, no additional treatment was started. Patient progressed to ESKD and was started on peritoneal dialysis in 2019.
      Thereafter she was again referred to our hospital because of preparation for kidney transplantation. In the interim, the patient had developed splenomegaly of unknown cause. Diuresis was 2300 ml/24h while on peritoneal dialysis. Laboratory examinations revealed a Hemoglobin level of 6.4 mmol/L, platelets 110 x109/L, leucocytes 5.3 x109/L, ferritin 270 μg/L, haptoglobin <0.10 g/L and a LDH of 587 U/L. Additionally, a monoclonal gammopathy IgM type kappa <2 g/L was found. Biopsy revealed a normocellular bone marrow with some lymphocyte aggregates and a remarkable histiocytosis without an increase of plasma cells or monotypic cells. Because of the cytopenias, hemolytic anemia, monoclonal gammopathy and splenomegaly, a genetic cause was suspected and a whole exome sequencing (WES) filtered for genes involved in clotting disorders, immunodeficiencies and kidney disease was performed. These analyses showed two heterozygous variants in each of the SLC7A7 genes, a missense variant (SLC7A7: Chr14(GRCh37):g.23248023T>A; NM001126105.2:c.749A>T; p.(Glu250Val); heterozygote (class 4)) and a splice site variant SLC7A7: Chr14(GRCh37):g.23245041C>A; NM001126105.2:c.998+1G>T; heterozygote (Class 5) in an evolutionary conserved sequence, raising the suspicion of LPI.
      Additional history showed that the patient had experienced symptoms after protein intake for all her life, consisting of nausea, vomiting and dizziness. She had also experienced recurrent viral and urinary tract infections during childhood and suffered from unexplained anorexia. There was no history of seizures or coma. However, she had apparently coped with these symptoms by changing her diet to a low protein intake. During peritoneal dialysis a high-protein diet was prescribed, however protein targets had to be consistently lowered due to intolerance. Metabolic testing revealed low plasma levels of ornithine, lysine and arginine (Table 1) which have been described to be normal in patients on peritoneal dialysis[
      • Kopple J.D.
      • Blumenkrantz M.J.
      • Jones M.R.
      • Moran J.K.
      • Coburn J.W.
      Plasma amino acid levels and amino acid losses during continuous ambulatory peritoneal dialysis.
      ]. Urine analysis showed elevated excretion of ornithine, lysine, arginine and tetraglucoside. These findings confirmed the diagnosis of LPI in our patient. She was started on a low-protein diet and was prescribed citrulline, which prevents the amino nitrogen and ammonia-induced hyperammonemia in LPI patients [
      • Rajantie J.
      • Simell O.
      • Rapola J.
      • Perheentupa J.
      Lysinuric protein intolerance: a two-year trial of dietary supplementation therapy with citrulline and lysine.
      ]. Sodium benzoate was omitted because of ESKD, as this acts by forming substance with glycine that can be renally excreted.
      Table 1Relevant amino acids, ammonia, renal function and ferritin as measured in plasma and urine before and after kidney transplantation.
      Plasma1 year before kidney transplantation*1 month after kidney transplantation8 months after kidney transplantation.

      After cessation of citrulline
      Reference range
      Ornithine (μmol/l)2912923**24 - 168
      Lysine (μmol/l)6319823769 - 252
      Arginine (μmol/l)20784416 - 125
      Citrulline (μmol/l)1191213011 - 46
      Glutamine (μmol/l)1067703909304 - 750
      Glutamic acid901165922 - 196
      Ammonia (μmol/l)323419<50
      Creatinine (μmol/l)***7672> 90
      CKD-EPI (ml/min/1,73m2)***7782> 90
      Ferritin (μg/L)63199816120 - 300
      Urine
      Ornithine (μmol/mmol creatinine)25200 - 4
      Lysine (μmol/mmol creatinine)771041 - 40
      Arginine (μmol/mmol creatinine)33400 - 7
      Citrulline (μmol/mmol creatinine)147600 - 2
      Glutamine (μmol/mmol creatinine)106447316 - 90
      Glutamic acid (μmol/mmol creatinine)6211 - 10
      Tetraglucoside (μmol/mmol creatinine)53.9-0.80 - 2
      Orotic acid (μmol/mmol creatinine)12-0 - 3
      *Without citrulline supplements, these were ceased 4 months after kidney transplantation.
      **Plasma ornithine was 33 umol/L 7 days before the measurement 8 months after kidney transplantation.
      *** Patient on peritoneal dialysis, normal diuresis.
      After establishing the diagnosis of LPI, the diagnosis of hemochromatosis was reconsidered, because LPI can cause high ferritin levels due to excess macrophage activation. Furthermore the patient had compound heterozygous HFE gene mutations (Cys282Tyr and His63Asp) with a very low described penetrance of only 0.5-2%, therefore a diagnosis of hemochromatosis was improbable [

      Barton JC, Edwards CQ. HFE Hemochromatosis. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA), 1993.

      ]. The ESKD in the patient was presumably also due to LPI. Kidney involvement is common in LPI and kidney biopsies did not suggest a specific primary or secondary kidney disease. that resulted in ESKD. She was accepted for potential kidney transplantation. Possible anticipated complications during and after surgery were excessive bleeding due to thrombocytopenia and thrombocytopathy, a catabolic state or hyperammonemia. To prevent bleeding shortly before surgery a platelet transfusion was administered as well as tranexamic acid which both would be repeated if necessary. In order to prevent a catabolic state a glucose 10% infusion of two liters per 24h was administered and ammonia levels were monitored regularly during and after surgery. In the event that ammonia levels were elevated during surgery, the plan was to administer sodium benzoate and arginine hydrochloride, as supplementation for the urea cycle. Citrulline was continued after transplantation.
      Kidney transplantation was performed in 2021 from a non-heart beating donor. No excessive bleeding, catabolic state or high levels of ammonia were observed under the aforementioned precautionary measures. After kidney transplantation protein tolerance increased significantly. Protein intake could be increased from 0.5 g/kg/day to the normal range of 1.0 g//kg/day without increasing symptoms. Three months after transplantation citrulline treatment was tapered and eventually could be stopped at 6 months. As of now, the patient experiences no symptoms after protein intake. Plasma levels as well as urinary excretion of ornithine, lysine and arginine normalized after transplantation and remained normal after the cessation of citrulline (Table 1). Ferritin levels after transplantation significantly decreased, demonstrating an impact on hematological parameters as well.

      Discussion

      Renal involvement with progression to ESKD is a severe complication of LPI [9 10 15]. Our case demonstrates several interesting insights in this rare metabolic disorder and the value of kidney transplantation in this patient.
      First, a kidney transplant at least partially normalized the metabolic profile in this patient with LPI. Due to the defect of the y+LAT1 transporter in LPI patients, reabsorption of ornithine, lysine and arginine in the proximal tubule is compromised, leading to loss of these amino acids via the urine [
      • Kurko J.
      • Vaha-Makila M.
      • Tringham M.
      • et al.
      Dysfunction in macrophage toll-like receptor signaling caused by an inborn error of cationic amino acid transport.
      ]. This renal wasting of amino acids could be attenuated in CKD, however plasma ornithine, lysine and arginine in our patient were still lower than in other PD patients [
      • Kopple J.D.
      • Blumenkrantz M.J.
      • Jones M.R.
      • Moran J.K.
      • Coburn J.W.
      Plasma amino acid levels and amino acid losses during continuous ambulatory peritoneal dialysis.
      ]. After kidney transplantation renal losses likely dissipates because the y+LAT1 transporter is functioning normally in the transplant kidney. This was evident in our patient who could increase her protein intake to normal levels and could stop taking citrulline. Amino acid plasma tests after kidney transplantation showed normal values for ornithine, lysine and arginine as well as normal urinary excretion of these amino acids, suggesting that the persisting gastrointestinal defect in amino acid absorption is overcome by correcting the renal defect. Tubular proteinuria along with a partial Fanconi has been described in LPI, probably due to excessive urinary loss of lysine which inhibits tubular protein uptake [
      • Benninga M.A.
      • Lilien M.
      • de Koning T.J.
      • et al.
      Renal Fanconi syndrome with ultrastructural defects in lysinuric protein intolerance.
      ].
      Secondly, it shows how heterogeneous the phenotype and, therefore, difficult the diagnosis of a rare disease like LPI can be and emphasizes the potential benefit of performing genetic analysis (e.g. WES) in a patient with unexplained disease [
      • de Haan A.
      • Eijgelsheim M.
      • Vogt L.
      • Knoers N.
      • de Borst M.H.
      Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology.
      ]. Our patient experienced symptoms from the start of life, however the diagnosis was never considered until the age of 52. Furthermore, the symptoms she experienced because of protein intolerance went unnoticed, through years of visiting medical specialists, until she was referred to a metabolic expert after the genetic diagnosis had been established. Performing a WES could have helped diagnose this disease earlier. This can be especially important in patients with longstanding unexplained symptoms where genetic testing was not available earlier in their disease course. Furthermore it is important to establish a definitive diagnosis comprising more than a phenotypical or pathological description. In our patient a presumed diagnoses of fibrillary glomerulonephritis was made based on kidney biopsy. However this is not a kidney disease in itself, and no disorder known to cause glomerular fibril deposits had been diagnosed.
      To our knowledge, this is the first report of a case of improvement in LPI symptoms and protein tolerance after kidney transplantation. Two Finnish case series described a total of five patients with LPI in whom a kidney transplantation was performed [9 11]. However, dietary intake of protein was kept unchanged after transplantation, nor was the dose of citrulline tapered, and amino acid levels after kidney transplantation were not reported.
      In summary, we describe a rare case of kidney transplantation in a patient with LPI where transplantation was associated with improvement in LPI symptoms. In addition, after transplantation, the patient’s protein intake could be increased and the dose of citrulline tapered and discontinued. Further studies are required to generalize these findings to other LPI patients.

      Uncited reference

      • Camargo S.M.
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      • Karki M.
      • Nanto-Salonen K.
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      Urine Beta2-Microglobulin Is an Early Marker of Renal Involvement in LPI.
      ,
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      • Bednarek N.
      • Vuiblet V.
      • et al.
      Renal Involvement in a French Paediatric Cohort of Patients with Lysinuric Protein Intolerance.
      .

      Article Information

      Support: none
      Financial Disclosure: The authors declare that they have no relevant financial interests.
      Patient Protections: The authors declare that they have obtained consent from the patient reported in this article for publication of the information about her that appears within this Case Report.
      Peer Review: Received February 24, 2022. Evaluated by 3 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form August 5, 2022.

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