Correspondence *Department of Pediatric Nephrology, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany

Email dominik.mueller@charite.de

The case

A 16-year-old white male presented to a pediatric outpatient clinic with a first syncope. His physical examination was normal: there were no symptoms of cardiac, cerebral or pulmonary abnormalities. At admission, the patient had an elevated blood pressure of 140/120 mmHg. His red blood cell count showed erythrocytosis (7.0 10¹²/l), a raised hemoglobin level of 220 g/l and an increased erythropoietin level of 27.4 U/l (normal: 1.5–15.2 U/l), but he had normal values for platelet and leukocyte counts. The patient had a history of obstructive uropathy that had necessitated repeated urological intervention. Soon after birth, he had been diagnosed with bilateral vesicoureteral reflux grade IV–V. At the age of 2 months, the patient underwent his first ureteral reinsertion on the left side; this procedure was repeated at 1.5 years of age and again at 8 years of age. Ureteral reinsertions on the right side were performed at the ages of 1.5 years and 2 years. Despite these interventions, the patient developed bilateral hydronephrosis as shown by renal ultrasound and MRI (Figure 1). A ^99mTc-MAG3 (technetium-99m-labeled mercaptoacetyltriglycine) scintigraphy of the kidneys at initial presentation at the age of 16 years demonstrated a nonfunctioning right kidney (Figure 2). Two years before presentation to the outpatient clinic, the patient's red blood cell count had been normal (5.76 10¹²/l); however, at the current presentation, it had increased to 7.0 10¹²/l. On admission to the outpatient clinic, the patient's creatinine level was 200.7 mol/l (2.27 mg/dl) and his estimated glomerular filtration rate was 45 ml/min/1.73 m² (Schwarz formula). Primary pulmonary disorders, cardiac disorders and tumors were ruled out by chest X-ray, echocardiography, electrocardiogram, abdominal ultrasound and confirmation of normal differential leukocyte count and normal serum concentrations of lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, electrolytes and platelets. The isolated increased erythropoietin level and subsequent clinical course also excluded polycythemia vera. Serial phlebotomies were performed on days 3, 7 and 9 after admission and resulted in a transient fall in red blood cell count and an increase in erythropoietin levels to 80.9 U/l. The patient's arterial hypertension was controlled with ramipril, nifedipine, hydrochlorothiazide and amlodipine. A ureteral stent was placed 9 days after admission to drain the urine of the left (functioning) kidney, and 13 days after admission, laparoscopic nephrectomy of the right (nonfunctioning) kidney was performed. During surgery, massive hydronephrosis of the right kidney bulging into the right lobe of the liver (Figure 1) was confirmed. At this time, the patient's serum erythropoietin level was 83.7 U/l in the right renal vein; a few minutes later it was 41.9 U/l in the peripheral brachial vein. The difference in erythropoietin levels between these veins indicated that the right kidney was the area of the excessive erythropoietin production. One day after surgery, the patient's serum erythropoietin levels and hemoglobin values had decreased; 2 days after surgery, they were normal (Figure 3). Hemoglobin levels remained normal over 3 months of follow-up.

Figure 1 Magnetic resonance image of the urogenital tract at presentation, demonstrating massive hydronephrosis of both kidneys

(A) Transverse T₂-weighted image. (B) Frontal T₁-weighted image. (C) Frontal T₂-weighted image.

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Figure 2 Renal clearance with ^99mTc-MAG3 scintigraphy demonstrating the absence of function in the right kidney

(A) The distribution of the ERPF in the right and left kidneys of this patient. (B) Dorsal image showing reduction of tracer activity in the right kidney 10 minutes after ⁹⁹Tc-MAG3 injection. The color scale to the right of the image indicates the amount of tracer of the region of interest (red: highest; purple: lowest). (C) Time course of tracer uptake and tracer wash-out by the kidneys. Intravenous furosemide administration (32 mg; 0.5 mg/kg) at minute 19 did not increase tracer elimination. Abbreviations: ⁹⁹Tc-MAG3, technetium-99m-labeled mercaptoacetyltriglycine; ERPF, effective renal plasma flow.

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Figure 3 Follow-up of the patient's hemoglobin levels and erythropoietin concentrations in the serum before and after nephrectomy of the right kidney

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Discussion of Diagnosis

Renal anemia is common in chronic kidney disease and usually results from insufficient renal production of erythropoietin.¹ Although they have not yet been identified, it has been reported that dialyzable inhibitors of erythropoiesis are present in the sera of patients with uremia.² Erythropoietin, a glycoprotein growth factor, is the primary stimulus for erythropoiesis, and promotes the proliferation and terminal differentiation of erythrocyte precursor cells into normoblasts and, subsequently, erythrocytes.³ Erythropoietin is produced by the kidney and to a much lesser extent by extrarenal tissue, mainly the liver. The primary source of erythropoietin synthesis seems to be renal interstitial fibroblasts, although some studies have indicated that proximal tubular cells also have an important role.^{4, 5, 6} Kidney cells expressing erythropoietin messenger RNA are limited to the deep cortex and outer medulla of the kidney under normal physiological conditions. Erythropoietin production is regulated by alterations in tissue oxygen tension.¹ Decreased oxygen delivery, most often a result of anemia or hypoxia, is the primary stimulus for erythropoietin production and release.³ As there is no significant store of erythropoietin,¹ the rate of de novo protein synthesis and its control are crucial. Events downstream of the oxygen-sensitive transcription factors are involved in erythropoietin gene expression, including the production of specific transcription factors such as hypoxia-inducible factor 1 (HIF1) comprising both alpha and beta subunits.⁷ The regulation of the HIF1 subunit occurs through oxygen-dependent degradation mediated by the von Hippel-Lindau protein (pVHL). In the presence of oxygen, pVHL binds to the HIF1 protein and targets HIF1 for proteasomal destruction.⁸ When local oxygen tension is low, HIF1 cannot be hydroxylated and binds to an enhancer sequence region on the erythropoietin gene, leading to an increase in the erythropoietin production.⁷ During anemia, cells expressing erythropoietin messenger RNA increase in number and their prevalence increases in the superficial cortex.⁵ In severe anemia, the serum erythropoietin level can be elevated to as much as one thousand times the normal level. A hypoxic stimulus increases the number of erythropoietin-producing cells in the cortex of the kidney, but not the amount of erythropoietin produced per cell.⁹

Secondary polycythemia, as occurred in the present case, is caused by an increased serum erythropoietin level. This disorder is most often a result of a compensative, oxygen-sensitive erythropoietin response to either hypoxia (e.g. cardiac or pulmonary diseases, exposure to high altitude) or high oxygen affinity hemoglobinopathies,^{10, 11} but it can also result from the presence of an erythropoietin-secreting tumor (e.g. Cushing's syndrome), self-injection of erythropoietin or hormonal stimulation of erythropoiesis (e.g. therapy with corticosteroids or androgens). In rare cases, dysregulated renin–angiotensin system feedback mechanisms, such as those seen in patients after renal transplantation, and elevated levels of insulin-like growth factor 1 have also been shown to stimulate erythropoiesis and cause secondary polycythemia.^{12, 13, 14}

In patients with renal insufficiency associated with increased hemoglobin levels and polycythemia, the possibilities of recombinant erythropoietin overdosing and disorders such as neoplasms and polycythemia vera must be excluded.

The present case and others in the literature indicate that the presence of hydronephrosis, even if associated with no apparent glomerular filtration rate (i.e. 'nonfunctioning kidneys'), must be added to this list of differential diagnoses.

Table 1 summarizes the published reports on patients with erythrocytosis, elevated erythropoietin levels and hydronephrosis. One retrospective study evaluated 355 patients with hydronephrosis (150 males and 205 females), and showed that 11.8% of patients had erythrocytosis. Red blood cell counts decreased to normal levels in 10 cases following nephrectomy.¹⁵ Another retrospective study found that 6 of 50 patients (12%) had hydronephrosis-associated polycythemia.¹⁶ Jaworski et al. reported a case in which drainage of the hydronephrotic kidney caused an immediate drop in hemoglobin concentration.¹⁷

Table 1 Overview of reported cases of resolution of polycythemia before and after treatment of hydronephrosis by nephrectomy

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In the present case, erythropoietin levels were determined simultaneously in the right renal vein (83.7 U/l) and in a peripheral brachial vein (41.9 U/l). The difference between these erythropoietin serum levels indicated that the right kidney was the source of the excessive erythropoietin production. Some case reports have found no erythropoietin activity in the renal vein or in venous or arterial blood,¹⁷ but it has been suggested that such findings were a result of assays employed by older studies lacking sensitivity to detect erythropietin.¹⁸ In the case presented here, the erythropoietin level was determined by the IMMULITE^® 1000 (Cirrus Diagnostics Inc., Los Angeles, CA, USA), a solid-phase chemiluminescent immunometric assay.

Our case and others reported in the literature indicate that pressure on the renal tissue develops slowly in hydronephrosis, leading to the local ischemia that stimulates erythropoietin production. In this condition, the tissue is compressed or stretched but not destroyed. As a result, the affected area becomes ischemic, stimulating an increase in erythropoietin-producing cells. This explanation is in line with the findings in a range of animal models of experimental hydronephrosis. In rabbits, erythropoietic response is most pronounced with low pressure or intermittent hydronephrosis rather than high pressure hydronephrosis.¹⁹

Thus, ureteral obstruction with slowly progressive hydronephrosis (as in the patient described here) can compress the renal tissue and reduce its blood and oxygen supply, resulting in increased erythropoietin production secondary to local renal ischemia. At present, it is unknown which cells in the damaged organ are responsible for increased erythropoietin production in a hydronephrotic kidney. In patients with cystic renal diseases (in whom mild or no anemia with elevated erythropoietin levels can occur), however, interstitial cells have been shown to express erythropoietin messenger RNA, even in advanced chronic kidney disease; cysts derived from proximal tubules, but not those derived from distal tubules, contained increased concentrations of bioactive erythropoietin.²⁰

Since hydronephrosis is more common than hydronephrosis-associated erythrocytosis, however, it seems unlikely that the distension and compression of renal parenchyma are the only factors responsible for erythrocytosis. Elucidation of the roles of additional factors, especially local hypoxia-inducible factors such as HIF1 and pVHL, might give new insights into renal erythropoietin regulation and ultimately lead to innovative pharmacological manipulations of erythropoietin production in the native kidneys.

Discussion of treatment

The case described here demonstrates a preserved feedback mechanism, as phlebotomies were followed by increased erythropoietin production. An autonomous mechanism, as seen in malignancy-associated polycythemia, could therefore be excluded. Erythropoietin measurements in the renal vein showed that the nonfunctioning kidney was the source of the excessive erythropoietin production. Removal of this kidney, therefore, terminated polycythemia. This finding is consistent with cases described in the literature in which removal of a kidney was followed by a significant drop in erythropoietin levels and the disappearance of polycythemia (Table 1).

Conclusion

In rare cases, hydronephrotic kidney disease can be the cause of erythropoietin-associated secondary polycythemia, even in nonfunctioning kidneys.

References

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additional references for cases shown in Table 1.

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Subject areas under which this article appears: Pediatric nephrology | Other