A 32-year-old male patient presented the clinical picture of loin pain haematuria syndrome with pain attacks accompanied by macrohaematuria. In renal biopsy, the preglomerular vessels showed segmental wall hyalinosis in the sense of low-grade nephrosclerosis, and glomerular capillaries with slightly but diffusely thickened, non-split basal membranes on electron microscopy. Notable were irregularly deformed, different dense erythrocytes in the glomerular capillaries, and several tubular lumina. The suspicion of erythrocytic enzyme deficiency could be confirmed. The enzyme activities of the erythrocytes were predominantly normal or slightly increased; only the activity of triosephosphate isomerase, a critical key enzyme of glycolysis, was reduced to 71% (resp. 57%) of the normal level, compatible with a heterozygous carrier status that could not be found. Patients with genomic triosephosphate-isomerase deficiency have degraded enzyme activities in virtually all tissues, such as leucocytes, platelets, and muscle cells. An association with neuromuscular symptoms is also known. Thus, it is possible that smooth muscle and intrarenal vascular spasms trigger clinical symptoms consisting of flank pain and phases of macrohaematuria. An aspirin-like defect (thrombocytopathy) had previously been found in connection with epistaxis (also due to TPI deficiency?). Enalapril treatment drastically reduced the frequency of macrohaematuria and pain attacks decreased to a lesser extent.

© 2022 The Author(s). Published by S. Karger AG, Basel

Loin pain haematuria syndrome (LPHS) is a rare disease with a prevalence of 0.012% [1] and is characterized by unilateral flank pain combined with micro- or macrohaematuria. It does not appear to be a single entity, and Spetie et al. [2] distinguish between secondary LPHS (as IgA-nephropathy) and idiopathic (primary) LPHS. Since the initial publication in 1967 by Little et al. [3], it has been, for a period of 14 years, a gender specific female syndrome [4]; later, male patients have caught up in number [5, 6]. LPHS is a descriptive diagnosis that remains after a comprehensive clinical investigation [7]. Up to now, the pathogenesis is unclear. Pain attacks have been described as severe to extremely severe and have led to a spectrum of non-surgical therapeutic strategies [4]: analgesics including opioids, ACE-inhibitors [8], nerve blockade [9, 10], dorsal root ganglion stimulation [11, 12], intraureteric capsaicin [13], etc. Surgical strategies range from renal autotransplantation [14, 15] to bilateral nephrectomy [16]. Autotransplantation is not unchallenged [17], but a report from French physicians is interesting: of 10 patients with LPHS, 5 required autotransplantation, two of whom finally underwent nephrectomy and gave their consent to transplantation of their nephrectomized kidney. In these two cases, neither the pain moved with the kidneys nor the haematuria [18]. More details on LPHS are given in several reviews [1, 4, 5, 8, 19], and several hypotheses regarding the pathophysiology are reviewed [1, 14, 20, 21]; these include the disease of renal arteries, coagulopathy, complement activation, renal capsular distension, abnormal ureteral peristalsis, abnormalities in the glomerular basement membrane, intratubular calcium or uric acid deposition, and psychopathological aspects. If, as in our patient, LPHS is combined with triosephosphate-isomerase deficiency (TPID), this could mark a new pathophysiological entity.

TPID is a worldwide autosomal recessive disease [22], with a prevalence of 3.7/1,000 in Germany [23, 24] and thus more common than the LPH syndrome. Only heterozygotes have a chance of survival. The first description was published in 1965 [25] by Arthur S. Schneider, who also published a review in 2000 worth reading [22]. Orosz et al. [26] also contributed new metabolic aspects. It was suggested that the original mutation occurred more than 1,000 years ago, probably by an ancestor who dwelt in England or France. TPI is an enzyme expressed in all tissues and encoded by a single gene located on chromosome 12p13. Heterozygotes can be biochemically identified by intermediate enzyme deficiency [22] and may result in a discrete haemolysis phenotype, an aspirin-like defect in platelets, involvement of skeletal and smooth muscles, including vascular smooth muscle and potential involvement of lipid metabolism [22]. The OMIM number of the TPID is: #615512.

The family history of our male patient with Huguenot ancestors offers a special feature: his father died of the consequences of Creutzfeldt-Jakob disease1. Our patient experienced a dramatic epistaxis episode at the age of 20. An accurate coagulation analysis revealed an aspirin-like defect1, a pathologic pattern (inhibition) of platelet aggregation could be demonstrated (induced by collagen, ADP, and adrenaline). He experienced back pain for the first time at the age of 29. Subsequently, a 2-year journey began through disciplines ranging from rheumatology to orthopaedics to psychiatry through outpatient and inpatient treatment. The patient was positive for HLA B27, but initially without clinical signs of ankylosing spondylitis. 16 months later, his back pain was combined for the first time with macrohaematuria, possibly triggered by phenylbutazone2. Urological examination was without pathologies in addition to slightly elevated serum-creatinine (1.4 mg/dL) and urine microscopy confirmed glomerular haematuria by red blood cell casts. We saw the patient for the first time in April 1996. At that time, s-creatinine was almost normalized. At a subaqual bleeding time (Marx test) of 60 s and normal plasmatic coagulation, a kidney biopsy could be performed. A triple diagnosis by light microscopy (LM), immunohistochemistry, and electron microscopy (EM) was performed. However, LM revealed normal glomeruli, in the lumen of some tubules dense accumulations of red cells, and in preglomerular vessels segmental wall hyalinosis in the sense of low-grade nephrosclerosis. IgM and C1q-complement immunohistochemistry were found within the wall hyalinosis, and some traces were found within the glomerular mesangium. Electron microscopically within the glomerular capillaries slightly, but diffusely thickened, non-split basement membranes were present. Furthermore, it was obvious that there were irregularly deformed erythrocytes of different density in the glomerular capillaries and several tubular lumina. These EM findings led to the suspicion of erythrocyte enzymopenia, which could be confirmed (Fig. 1; Table 1). As the previous urological evaluation did not disclose the cause of recurrent loin pain and haematuria, we excluded a disease of the renal arteries or veins by angio-CT. The clinical study revealed a labile hypertension with nocturnal dipping. Blood chemistry was normal except for slightly elevated s-creatinine (1.1 mg/dL) but lower than before (1.4 mg/dL). The measured endogenous creatinine clearance was 105 mL/min, corrected for body surface: 91 mL/min × 1.73 m2. The blood cell count for red cells was normal, as well as for white cells and platelets. The free haemoglobin in serum was slightly enhanced (6.5 mg/dL) as well as haptoglobin (333 mg/dL), ferritin was reduced (13.5 ng/mL) at normal red blood cell count (5.4 × 106/µL), and haemoglobin (15.7 g/dL).

Enzyme activities of the patient’s erythrocytes, measured as substrate turnover in µmol/g haemoglobin (erythrocyte haemolysate) at 37°C compared to a normal population. Whereas triosephosphate isomerase activity is reduced to about 71% and 57% at control, all other enzymes are normal or slightly enhanced (bold)

Glomerular capillaries with unusually tightly packed and deformed erythrocytes of varying density. Capillary walls and mesangium are normal (EM × 1.100). Similar casts of erythrocytes as in glomerular capillaries could be demonstrated in tubular lumina. At higher magnification (82,000 not shown) erythrocytes show coarse-granular structure without tactoid formations.

Urinalysis was normal during the attack-free interval, with microalbumin at the detection limit. In the follow-up over a period of 6 years, we saw acanthocytes in the urine sediment only once. We treated hypertension with enalapril, first recommended by Betts et al. (JASN 4, 270, 1993, abstract) for the treatment of LPHS [8]. This led to a drastic reduction in phases with gross haematuria but had only a little effect on the frequency of flank pain. Years later, magnetic resonance imaging revealed sacroileitis due to ankylosing spondylitis. The last contact with the patient in 2019 gave the opportunity to re-evaluate the presence of the enzymopenia in the same laboratory as in 1996 (A. Pekrun), and, in addition, we performed a search for TPI deficiency through genetic analysis in blood and a panel analysis for kidney diseases. Indeed, TPI in 2019 was 1,002 U/g haemoglobin (normal range now 1,400–2,100 U/g Hb), which in turn would be compatible with the heterozygous status of a TPI deficiency.

Genetic testing was carried out on a research basis after the written informed consent of the patient was obtained. For genetic analyses, DNA from blood cells was used. First, targeted Sanger sequencing for the TPI1 gene yielded unremarkable results. As, however, no heterozygous polymorphisms could be detected in the TPI1 sequence, the presence of heterozygous larger deletions/duplications could not be excluded with certainty. In a second step, the DNA was analysed via next-generation sequencing of a type B panel of 487 kidney disease-associated genes, including the TPI1 gene. This analysis again yielded no disease-causing mutations in the TPI1 gene as well as in the other 486 analysed kidney disease genes. More than 99% of the analysed regions were covered with a sequencing depth of at least 20x; regions with a covered sequencing depth of <10x were excluded from the analysis. The sequencing reads were mapped on the reference genome (GRCh37/hg19). The explorative bioinformatic quantitative analysis of the exon-specific sequencing depth of the TPI1 gene did not suggest the existence of deletions or duplications. The sensitivity of such an analysis is about 80–90%, and the specificity 90–95%. Pathogenic or likely pathogenic sequence variants in 487 genes associated with RKD could not be identified (Agilent Sure Select custom-designed enrichment gene panel run on a NextSeq500 [Illumina, San Diego, CA, USA]).

A recent literature review was negative for the co-occurrence of LPHS and TPI deficiency. This case was first published as an abstract in German in 1997 with the intention to find more cases [27]. Both LPHS and TPI deficiency are rare diseases, and maybe this report in English opens up new possibilities to identify more patients. If the combination of LPHS and TPI deficiency could be found repeatedly, this could be a key to understanding the disease and lead to the development of a unified pathophysiological concept.

In the case of homozygous carriers, the enzyme defect in erythrocytes leads to haemolytic anaemia, in leucocytes to recurring infections, and in the first year of life, neuromuscular disorders are added, which are the leading cause of early infantile death [24]. Partial TPID was detected in our heterozygous carrier – as previously thought [27]. This would have been a possible explanation for the morphological changes of erythrocytes observed in the tubular lumen (kidney biopsy), which had been the reason for looking for an enzymopathy. The penetration into the tubular lumen may be due to local vascular spasms, which lead to increased glomerular penetration of red blood cells through local hypoxia and ischaemia (Fig. 1). Enzyme deficiency could be the cause and a pathophysiological explanation for the vascular muscle spasms and the at times almost intolerable pain reported by the patient. In erythrocytes, glucose turnover is increased by substrate flux through the pentose phosphate shunt. The dihydroxyacetone phosphate increases. This substrate cannot drain into other pathways within red blood cells, but in muscle cells this substrate can be recycled via detours; whether it is enriched is not known.

The severe pain that has often led to autotransplantation of the kidney has repeatedly reappeared after autotransplantation [4], or in addition, the haematuria has been described to return to the autotransplanted kidney [15]. On the contrary, the 2 kidneys of LPHS patients transplanted to ESRD patients as a donation remained in the recipient with no return of loin pain or haematuria episodes [18]. Sollinger recently published the “UW-LPHS” test as a preoperative prediction of a successful outcome after renal autotransplantation [14] without recurrence of pain attacks or haematuria. These authors have longstanding experience, and the described test was said to definitively localize pain to the ureter, which provides a hypothesis that the ureter is the target organ. The test was based on an observation by Russell et al. [28] that Tadalafil can affect pain attacks by smooth muscle relaxation (also of the ureter). The developed UW-LPHS test uses ureteral infusion of bupivacaine. Combined smooth muscle spasms of the ureter and of the intrarenal arteries based on TPI deficiency would be the common denominator of a long-sought pathophysiological conundrum in the narrower sense of LPHS.

Another aspect of the family history of our patient is his father’s death. Creutzfeld-Jakob disease had been named as a suspected cause of death, but could also have been Alzheimer’s disease. TPI was identified as one of the main nitro tyrosinated proteins by nitric oxide synthase in Alzheimer’s disease, as discussed in the review by Orosz et al. [26]. In the cited work of Guix et al. [29] they showed that amyloid β-peptide-induced nitro-oxidative damage promotes nitro tyrosination of the glycolytic enzyme triosephosphate-isomerase in human neuroblastoma cells, etc. A recent study carried out in a mammalian model of TPI deficiency demonstrated that the haematologic phenotype could be saved by bone marrow transplantation [30].

This case history with the clinical picture of an LPHS and the detection of a reduced TPI enzyme activity of erythrocytes may indicate a connection, although we have not been able to demonstrate a carrier state for TPI deficiency in our patient and there may be other regulatory factors (mRNA processing?) that decrease TPI activity, which could be shown again first in 1996 and then more than 20 years later in 2019. More research is needed to improve our understanding of the pathophysiology of LPHS.

We dedicate this work to our honoured teacher, Professor Adalbert Bohle, Tübingen University (1922–1998), who would have turned 100 this year. We pay tribute to the nurse Elvira Heese in the “Nephrologisches Zentrum Emsland” for caring for the patient.

The prerequisite for this case description was the patient’s consent, which he gave in writing for the publication as an abstract in 1997 and to the Institute for Human Genetics in Cologne for the genetic analysis in 2019 in accordance with the https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Klicken oder tippen Sie, wenn Sie diesem Link Vertrauen. World Medical Association Declaration of Helsinki. Ethical approval for this single case report is not required for this study in accordance with local or national guidelines.

The authors have no conflicts of interest to declare.

Since the patient’s health insurance company did not cover the costs of the genetic analysis, one of the authors (HJS) reimbursed the costs to the Cologne Institute for Human Genetics.

Hans-Joachim Schurek, as a nephrologist, saw the patient for the first time in 1996, initiated the diagnosis, and prepared the case as a contribution (abstract) to the congress of the Society for Nephrology in 1997. The death of the co-author from 1997, Werner Schröter, in 2019 was the reason to reopen the case. The literature search revealed that no fundamentally new aspects had been added with regard to the pathophysiology of LPHS. That motivated me to now strive for the casuistry as an English-language publication in addition to current genetic diagnostics. HJS has prepared the manuscript. Peter Maisel, as family doctor and head of general medicine at the University Hospital in Münster, looked after the patient and encouraged genetic analysis more than 20 years after the initial diagnosis and the abstract from 1997, which I (Hans-Joachim Schurek) presented as a poster at the Nephrology Congress in Aachen. PM has contributed to the improvement of the English text. Udo Helmchen in 1996 assessed the kidney biopsy as a pathologist and gave the decisive indication of a possible enzymopenia of the erythrocytes, which then led to the diagnosis of TPI deficiency. Udo Helmchen was also a co-author in the 1997 abstract and contributed the EM image. Björn Reusch carried out the current genetic analyzes and was unable to detect any of the previously known mutations, also in a further in-depth analysis and the spectrum of pathogenetic sequence variants in 486 gene-associated RKDs (rare kidney disease). He formulated the genetic part of the work. Arnulf Pekrun carried out the enzyme analysis on the patient’s erythrocytes in his laboratory in Bremen both in 2019 and in 1996 during the initial diagnosis of TPID in the Göttingen laboratory of the Children’s University Clinic and has already published about TPID. His boss in Göttingen, Werner Schröter, was co-author of the abstract in 1997; his death in 2019 at the age of 85 was the reason for me (HJS) to reopen the casuistry.

All data that support the findings of this study are included in this article. All patient-related documents are stored in the archive of “Nephrologisches Zentrum Emsland.” A register of biopsy findings is archived permanently by a foundation in Hamburg and is managed in trust by the “Stifterverband für die Deutsche Wissenschaft.” This also applies to the described biopsy material from our patient.

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