Introduction
Nutcracker phenomenon (NCP), also known as left renal vein (LRV) entrapment, is caused by a compression of LRV between abdominal aorta and superior mesenteric artery (SMA). NCP is characterized by this specific anatomical condition which can be a normal variant or an incidental finding while nutcracker syndrome (NCS) describes LRV entrapment with clinical manifestations [1,2]. Recently, the prevalence and knowledge of NCS are increasing owing to increased attention to NCS and the development of several diagnostic techniques [2,3]. Although it is increasingly perceived, NCS is a challenging condition due to the lack of gold standards for its diagnosis and management [2].
NCS can occur at any age from children to older people. Patients with NCS may have a variety of signs or symptoms such as macro- or micro-hematuria, proteinuria, left flank or pelvic pain, varicocele, and anemia [4,5]. While NCS is known to be associated with a non-glomerular cause of hematuria, increased LRV pressure in NCP could lead to glomerular hematuria as well [6]. In addition, orthostatic proteinuria is a common feature of NCS [7]; however, all patients with NCS do not present postural proteinuria. Symptoms like micro- or macro-hematuria and/or proteinuria are also common findings in various glomerulonephritis (GN). Glomerulopathy such as minor glomerular abnormalities (MGAs) is frequently detected in patients with persistent isolated proteinuria or microscopic hematuria [8]. Notably, reports for combined cases of coexistence of NCS and GN have been steadily increasing, especially in immunoglobulin A nephropathy (IgAN) [3,9-11]. While these two conditions could be simply coincidental findings, several studies have shown the impact of renal venous pressure elevation and consequent renal congestion on renal hemodynamics, inflammation, and endothelial activation [12-14]. Congestive nephropathy has also emerged as an important cause of renal dysfunction that is associated with decreased renal perfusion and hormonal activation [14]. Therefore, renal venous congestion caused by NCP and/or NCS appears to be related to functional and histopathological changes in kidneys. Whether long‐term congestion will sustain renal disease progression to tubulointerstitial fibrosis remains unknown. Evidence on the diagnosis and management in combined cases of NCS and GN is also limited. Previous studies have rarely clarified the relationship between these two entities.
In the present study, we hypothesized that NCS could be a trigger factor for the development or aggravation of GN and examined clinical and pathologic findings in a case series of patients with NCS combined with biopsy-proven GN. Glomerular lesions were divided into two pathological categories: MGAs and definite GN. The causal or coincidental association between NCS and GN was investigated in pediatric patients presenting with proteinuria with or without hematuria.
Methods
Study population and evaluation
Clinical, radiologic, and pathologic findings of 15 patients under 20 years of age who were diagnosed with NCS and GN between May 2018 and January 2024 were retrospectively reviewed. Proteinuria and/or hematuria were initially detected on a school or daycare center health check-up except for two patients with IgA vasculitis nephritis (IgAVN). Orthostatic proteinuria was confirmed from the amount of protein measured at recumbent or standing position for 12 hours. Evaluation for orthostatic proteinuria was performed at least three or more times per year during the follow-up period for all patients. The estimated glomerular filtration rate (eGFR) was determined using the bedside Schwartz equation [15]. The annual eGFR decline rate was calculated from the difference between baseline eGFR and the latest eGFR divided by time interval in years [16]. Kidney Doppler ultrasonography (US) was initially performed and followed up at the time of aggravation or improvement of proteinuria and/or hematuria. Doppler US was done by two well-experienced pediatric radiologists in our medical center. Magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) was additionally performed for further confirmation of NCS, except for two patients. Kidney biopsy was done in all patients to evaluate GN. All kidney biopsies were done on the left kidney, except for one patient. Clinical, laboratory, and radiologic features as well as biopsy findings of all patients were summarized. Baseline characteristics and renal outcomes were also compared between patients with MGAs and those with definite GN.
This study was approved by the Institutional Review Board (IRB) of the Korea University Ansan Hospital (No. 2023AS0067). The IRB waived the requirement to obtain informed consent since this study involved a retrospective chart review of anonymous patient data. Patients’ data from our previous paper [17] were partially included.
Definition
Proteinuria was defined as urine protein-creatinine (Cr) ratio (uPCR) of ≥0.2 mg/mg and/or 24-hour proteinuria of ≥4 mg/m2/hr [18]. Microscopic hematuria was diagnosed as ≥5 red blood cells (RBCs)/high-power field (HPF). Orthostatic proteinuria was defined as the presence of proteinuria in the upright position while absence of proteinuria in the supine position (<4 mg/m2/hr) [19]. On kidney Doppler US, the NCS was diagnosed when the peak velocity ratio (PVR) between the aortomesenteric and hilar portion of the LRV was greater than 4.0 [9]. In abdomen CT or MRI, a reduced aorta-to-SMA angle of less than 35° and the anteroposterior diameter ratio of pre/post compressed LRV above 2.25 were criteria for the diagnosis of NCS [20]. MGA on kidney biopsy was defined as unclassified glomerular lesions with minor structural abnormalities insufficient for specific pathological diagnosis [8]. Left kidney enlargement was characterized by the presence of a renal length discrepancy >10 mm between the right and left kidneys (left kidney longer) by renal US, CT, and/or MRI [21].
Statistical analysis
Baseline characteristics are described using means ± standard deviations for continuous variables and numbers (%) for categorical variables. For comparison between the two groups, the Mann-Whitney U test was used for continuous variables and the Fisher exact test or Pearson chi-square test was used for categorical variables. Results with p-values of <0.05 were considered statistically significant. All statistical analyses were performed using R version 4.1.2 (R Foundation for Statistical Computing).
Results
Patient presentation
Case 1
A 14-year-old boy presented with proteinuria on a school health check-up and foamy urine for the past 2 weeks. He had a family history of nephrectomy (grandmother and aunt). His body mass index (BMI) was 16.4 kg/m2 (2nd percentile). Laboratory test results showed an elevated serum Cr level of 0.93 mg/dL (eGFR using the bedside Schwartz formula, 76.9 mL/min/1.73 m2). Complement 3 (C3) was reduced with a value of 81 mg/dL (reference range, 90–180 mg/dL), and C4 was normal (11.3 mg/dL; reference range, 10–40 mg/dL). IgA level was elevated with 300 mg/dL (reference range, 47–249 mg/dL). The results for anti-double-stranded DNA antibody (Ab), antinuclear Ab, antineutrophil cytoplasmic Ab, and anti-glomerular basement membrane (GBM) Ab were all negative. The uPCR was 0.97. Orthostatic proteinuria was excluded. Kidney Doppler US showed increased renal cortical echogenicity of both kidneys and compressed LRV at aortomesenteric angle with a PVR of 8.08, suggesting NCS. On kidney biopsy, MGA was revealed with focal foot process effacement (Fig. 1A, B). Since proteinuria was aggravated with a uPCR of 5.37 and serum C3 and C4 levels were reduced with the lowest level at 64 mg/dL and 7.1 mg/dL, respectively, oral steroids and angiotensin-converting enzyme inhibitor (ACEi) were started. Level of eGFR went down to 67.4 mL/min/1.73 m2. Kidney Doppler US showed the NCS for 4 years consecutively. Low levels of C3, C4, and high IgA concentration also persisted. Proteinuria was worsened or lessened depending on the steroid dose. Abdomen CT revealed an enlarged left kidney size together with NCP (Fig. 1C). At present, he is taking low-dose steroids and ACEi. An open surgery for NCP was recommended by the urologist, however, his parents refused to allow him to undergo surgery. The last follow-up eGFR was 80.8 mL/min/1.73 m2. The patient’s clinical course is shown in Fig. 1D.
Case 2
A 6-year-old boy presented with microscopic hematuria on a school health check-up. Urinalysis showed a high amount of hematuria (RBC, >60/HPF; dysmorphic RBCs, 80%) and proteinuria (uPCR, 0.94). During 1-year follow-up, uPCR fluctuated from 0.2 to 2.1 and dysmorphic RBCs in urine were frequently found (dysmorphic RBCs, 50% to 90%) with micro-hematuria. Kidney biopsy showed MGAs with mild foot process effacement. However, he showed severely fluctuating proteinuria with uPCR of 0.2 to 7.3 and normal serum protein level. Kidney Doppler US was not specific. Four years after the initial presentation, abdomen CT revealed NCS with an engorged left renal venous system. Enlarged sizes of the left kidney and left gonadal varicocele were detected (Fig. 2A, B). Follow-up Doppler US confirmed the presence of NCS with PVR of 5.07 and abdomen CT 1 year later persistently showed the presence of NCP (Fig. 2C, D). During the 6-year follow-up, the level of uPCR was inconsistent with that of 24-hour proteinuria. ACEi and oral steroids were not effective in this patient. His clinical course is shown in Fig. 2E.
Case 3
A 10-year-old girl presented with proteinuria on a health check-up. Seven years ago, she had visited our hospital for proteinuria (uPCR, 0.56) and micro-hematuria (RBC, >60/HPF). However, she was lost to follow-up after 3 months. Initial laboratory findings showed low serum protein (5.6 mg/dL) and high cholesterol level (223 mg/dL). She had a nephrotic range of proteinuria (uPCR, 3.95; 24-hour proteinuria, 55 mg/m2/hr) but no hematuria. Orthostatic proteinuria was excluded and NCS was revealed on kidney Doppler US (Fig. 3A). However, kidney biopsy also confirmed the presence of focal segmental glomerulosclerosis (FSGS) (Fig. 3B, C). She was treated with ACEi, steroids, and cyclosporine. Eighteen months later, her proteinuria was reduced (54 mg/day) and ACEi only was used. At that time, the NCS was not observed. However, her proteinuria waxed and waned thereafter (uPCR, 0.29–1.21). Kidney Doppler US showed the NCS again with a PVR of 7.43. Abdomen CT also confirmed the presence of NCS (aorta-to-SMA angle, 31°; compression ratio, 2.64). The patient’s clinical course is shown in Fig. 3D.
Summary of patients with nutcracker syndrome and glomerulopathy
Demographic, clinical, and laboratory features of a total of 15 patients with NCS and glomerulopathy are summarized in Table 1. Their mean age was 11 ± 3.36 years, and the proportion of males was 53.3%. Mean follow-up duration was 53.8 ± 29.3 months. Two out of 15 patients had BMIs under 5%, and the mean BMI was 18.9 ± 3.35 kg/m2 (32% ± 32.1%). Chief complaints at the initial visit were isolated proteinuria in six patients and proteinuria with microscopic hematuria in nine patients. Orthostatic proteinuria and isolated hematuria were absent in our case series. Two patients (cases 7 and 13) showed intermittent gross hematuria. Only four patients with proteinuria and hematuria were examined for urine RBC morphology. One of them showed non-glomerular hematuria (case 7). BP levels of all patients were within normal ranges. Four patients had a family history of kidney diseases (cases 1, 7, 10, and 14). Notably, the father of case 14 had a history of NCS combined with thin basement membrane disease (TBMD) in his late teens and the patient showed kidney biopsy findings of IgAN with diffuse thin GBM. Intermittent normochromic normocytic anemia was observed in four children (cases 1, 4, 7, and 15; range, 10.0–11.1 g/dL) and leukopenia in three patients (cases 5, 7, and 10; range, 3,150–4,380/mm3). C3 and/or C4 levels were reduced in four patients (cases 1, 4, 5, and 6; range: C3, 64–80 mg/dL; C4, 7.1–9.6 mg/dL) and serum IgA levels were elevated in four patients (cases 1, 12, 14, and 15; range, 250–354 mg/dL). Six patients (cases 6–8, 10, 12, and 14) showed intermittent low IgD levels (<0.63 mg/dL; reference, 0.77–13.2). While all patients showed no difference in kidney length at first, five patients developed left kidney enlargement (cases 1, 2, 6, 7, and 8; mean length difference of both kidneys, 13.3 mm). Extrarenal symptoms included left gonadal varicocele, a splenic cyst, syncope, palpitation, anemia, and left chest wall deformity. Eight patients were diagnosed with NCS at the initial US and seven children were detected during a follow-up with aggravation of proteinuria. Kidney Doppler US was performed at least two times in all patients except for two (cases 4 and 15). Three patients showed resolution and reappearance of NCS (cases 3, 5, and 9). Ten of 15 patients were taken kidney biopsy within 1 year from the initial presentation. MGAs in seven children, focal GN in one, mesangial proliferative GN in one, FSGS in one, IgAVN in two, and IgAN in three patients were diagnosed. To clarify pathologic findings, we performed a biopsy of the right kidney in one patient (case 7). Proteinuria has been fluctuating, and the correlation between uPCR and 24-hour proteinuria was not evident in some patients (Table 1).
Comparisons of clinical features and outcomes between patients with and without definite glomerulonephritis
To evaluate the causal or coincidental association between NCS and glomerulopathy, we compared the clinical features and outcomes of patients with MGAs and those with definite GN. Age, follow-up duration, BMI, baseline and lowest eGFR, immunological abnormalities, clinical features of NCS, extrarenal symptoms, and persistent proteinuria were all similar between the two groups. However, the proportion of isolated proteinuria was more common in children with MGAs than in those with definite GN (71.4% vs. 12.5%, p < 0.05) (Fig. 4A) and peak level of uPCR tended to be higher in the MGA group (3.57 ± 2.49 vs. 1.77 ± 1.38, p = 0.40) (Fig. 4B). Specifically, the last follow-up eGFR was significantly reduced in patients with MGAs compared to that in those with definite GN (90.3 ± 14.3 mL/min/1.73 m2 vs. 107 ± 15.6 mL/min/1.73 m2, p < 0.05) (Fig. 4C). The average annual eGFR decline rate of MGA and GN groups were 4.77 ± 2.48 and 4.11 ± 3.69 mL/min/1.73 m2 per year, respectively, which showed no difference between the two groups. Five patients without eGFR decline at the latest follow-up were excluded in this analysis. Most patients with definite GN were treated with immunosuppressive agents (ISAs) and ACEi. However, the management was more diverse in patients with MGAs (Table 2).
Discussion
In the present study, we report 15 cases of NCS combined with biopsy-proven GN presenting with proteinuria with or without hematuria. MGAs were most frequently found, followed by IgAN, IgAVN, and the same number of focal GN, mesangial proliferative GN, and FSGS. Almost all patients showed unusual clinical courses in comparison with biopsy findings. Isolated proteinuria was more common in the MGA group. The correlation between spot uPCR and 24-hour proteinuria was inconsistent in some patients. A more considerable reduction in eGFR on the last follow-up was revealed in children with MGAs compared to those with definite GN. Associations of NCS with various GN should be considered in patients with persistent proteinuria with or without hematuria. A close long-term follow-up is needed for patients with these two combined conditions.
Patients with NCS have been shown to correlate with a low BMI. A lack of supporting mesenteric fat, which reduces the aortomesenteric angle, is one possible contributor to the development of NCP [20]. Renal ptosis, in which the kidney descends into the pelvis with the position change from supine to upright, has been proposed as another etiology of NCP [20]. LRV stretching over the abdominal aorta and venous congestion may be worsened by a lack of supporting retroperitoneal fat [20,22]. Common manifestations of NCS-hematuria, proteinuria, and flank/pelvic pain- are probably related to renal venous congestion and increased LRV pressure [20]. Venous hypertension and collateralization in NCS can also cause left-sided varicocele in males and pelvic congestion in females [20,22]. Although rare, symptoms and signs related to autonomic dysfunction may occur, including orthostatic hypotension, dizziness, and syncope [5,23]. Cases of a splenic cyst and splenic vein enlargement have also been described [4,24]. Compared to this epidemiology, the BMI below the 5th percentile was found in only two out of 15 patients in the present study. While hematuria and orthostatic proteinuria are relatively common in the NCS [4], isolated hematuria and orthostatic proteinuria were absent in our patients. Atypical presentations such as a splenic cyst, left gonadal varicocele, syncope, anemia, etc. were observed. While persistent severe hematuria is considered as a cause of anemia in the NCS [25], sustained hematuria was present only in one (case 7) out of four patients with anemia. Given that anemia is often associated with clinical signs of congestion [26], renal congestion induced by NCP can compromise microvascular blood flow, which may contribute to renal hypoxia, ineffective erythropoiesis, and resultant anemia [27].
Diagnosis of NCS can be confirmed by kidney Doppler US, contrast-enhanced CT, MRI, and venography. The first imaging tool with suspected NCS is Doppler US [25]. Although venography is considered the gold standard for the diagnosis of NCS, it remains unclear whether the invasive procedure for measuring the pressure gradient is truly needed [20]. In our cases, all patients were initially diagnosed with kidney Doppler US. Instead of venography, CT or MRI was additionally performed except for two patients. Some patients who had presented with NCS from the beginning showed resolution and reappearance of NCS depending on the level of proteinuria. Others who had been diagnosed with GN revealed the NCS later along with persistent proteinuria with or without hematuria. In case 2, Doppler US was ineffective for the initial diagnosis of NCS. We were able to confirm the NCS with abdomen CT. Since the proliferation of fibrous tissue at the origin of the SMA and increase of retroperitoneal adipose tissue can occur during normal growth, the LRV entrapment between SMA and abdominal aorta may appear or disappear, affecting proteinuria and/or hematuria [28]. Therefore, the relevance between the NCS and clinical course in our series is plausible. The presence of NCP and/or NCS should be suspected in children with persistent proteinuria.
Notably, the coexistence of NCS and GN has been increasingly reported in the past 15 to 20 years. Among them, IgAN and IgAVN were common conditions in patients with NCS and various GN [3,10]. Other than IgAN, a case of NCS combined with TBMD in a 21-year-old woman presenting with persistent flank pain and a larger left kidney has been reported [9]. She showed a higher proteinuria than typical cases of TBMD. Interestingly, the father of one patient (case 14) with NCS and IgAN in our case series had a history of NCS combined with TBMD in his late teens. NCS complicated by membranoproliferative GN or moderate mesangial hypercellularity was also reported in patients with sustained proteinuria [11,29]. Notably, an acute increase in renal venous pressure from renal vein constriction can cause an elevation of renal interstitial hydrostatic pressure, a reduction of renal blood flow, and a subsequent decrease of GFR via the renin-angiotensin system (RAS) [30]. Compression of peritubular capillaries and tubules, renal hypoxia, and physical stress caused by the left kidney congestion could induce pericyte detachment, which may possibly lead to extracellular matrix expansion and tubular injury [12]. Emerging evidence also indicates that a low renal perfusion pressure can negatively impact renal function and histopathology with time [14]. Meanwhile, within the nephron, venous hypertension is associated with the activation of a subclinical immune cascade in the vessel wall [31]. Venous congestion induces vascular stretch, which can activate vascular endothelial cells [13]. Endothelial cells actively participate in innate and adaptive immune responses, including complement production and control and pro-inflammatory, pro-oxidant, and vasoconstricting responses [32]. Immunomodulatory endothelial cells in the kidney may closely interact with resident immune cells, which are involved in rapid responses to circulating immune complexes [32]. It is well known that immune complexes containing galactose-deficient IgA1 play a crucial role in the pathogenesis of IgAN. While the pathogenesis of IgA vasculitis remains largely unknown, it has been proposed that in IgA vasculitis, IgA1 antibodies against endothelial cells are produced. Such IgA complexes can activate neutrophils via the IgA Fc receptor, thereby causing tissue damage [33]. Intriguingly, glomerular IgA and galactose-deficient IgA1 deposition were more commonly reported in patients with NCP than in those without NCP [10]. In the present study, our patients with NCS showed various kidney biopsy findings of MGAs, IgAN, IgAVN, focal GN, mesangial proliferative GN, and FSGS. While MGA was most often diagnosed, IgAN and IgAVN were common in the next order. Immunologic alterations such as leukopenia, high IgA level, and low C3/C4 and IgD concentration were also found in 64% of our patients. IgD is known as a key regulator for balanced Ab responses [34], and defective IgD function can result in deregulated activation of B cells and impaired immune responses [34]. In an animal experiment, lupus mice with IgD deficiency showed elevated autoAb production, increased immune complex deposition, and more severe nephritis [35]. Therefore, decreased IgD level might be involved in abnormal immune responses in our clinical context. Collectively, elevated LRV pressure by NCP may increase glomerular and interstitial hydrostatic pressure, decrease renal blood flow, and activate vascular endothelial cells. All of these can synergistically contribute to glomerular or tubular damage and extracellular matrix expansion. They may also induce RAS activation, renal hypoxia, pericyte loss, and alteration of mucosal immunity. Dysregulated activation of the immune system in our case series can contribute to the genesis or worsening of various glomerular lesions.
Treatment options for NCS should be based on the severity of symptoms and expected reversibility according to the patient’s age [4,20]. For children with NCS only, the first-line management is a conservative approach. ACEi can be used for cases with severe and prolonged proteinuria [20,29]. Surgery may be considered for a frustrated conservative approach with severe symptoms [4]. In adults, the gold standard of care is LRV transposition with or without renal autotransplantation. However, it has disadvantages such as severe bleeding, vessel thrombosis, LRV restenosis, etc. [4]. Due to its minimally invasive nature, endovascular or laparoscopic extravascular stenting can be an alternative treatment of choice in managing NCS [4,20]. In our patients presenting with NCS and glomerulopathy, surgical procedures were not performed. Instead, all patients except three were treated with ACEi with/without ISAs. While some patients did not improve with ISAs including steroids, others showed worsened proteinuria after quitting ISAs. Particularly, patients with C activation or immune dysregulation showed good responses with ISAs. Meanwhile, fluctuating GFR and renal dysfunction have been reported in patients with NCS [36,37]. In the present study, fluctuation of uPCR was severe in some children with MGAs. Proteinuria with or without hematuria persisted for a long time relative to renal biopsy findings in almost all patients. Baseline and lowest eGFR tended to be lower while uPCR tended to be higher in the MGA group than in the definite GN group. The last follow-up eGFR was more reduced in patients with MGAs than in those with definite GN even though the annual decline rate of eGFR was not different between the two groups eventually. Given that the relevance of MGAs and renal function decline has been suggested in previous studies [8,38], clinicians should pay attention to not only patients with definite GN but also those with MGAs. Older age and less aggressive therapy with ACEi and/or ISAs in the MGA group—although the differences were not statistically significant—could affect these results. To put it simply, MGA could be a secondary change of NCS and definite GN would be a coincidental finding with NCS. Nevertheless, the annual eGFR decline rate in both groups was more than 3 mL/min/1.73 m2 per year, which is often defined as rapid kidney function decline [39,40]. This rate of kidney function decline has been shown to be associated with an increased mortality risk, especially in older adults, irrespective of the presence of chronic kidney disease at baseline [39,40]. In our clinical context, the dual burden of NCS and glomerulopathy may contribute to the rapid decline in eGFR. Since five out of a total of 15 patients did not show a decline in eGFR at the last follow-up, sustained long-term observations are needed to determine the presence of kidney function decline.
Of note, the clinical findings of NCS often might overlap with various GN [25]. There is no consensus on management in patients with combined LRV entrapment and GN. A potential overlap of these two conditions should be considered in patients with persistent proteinuria and/or hematuria even after treatment [3,25]. In our case series, we identified some cause-and-effect relationships between NCS and GN, such as renal histologic alterations, immune dysregulation, and renal function decline. NCS might induce MGAs, focal GN, mesangial proliferative GN, and FSGS consecutively. It can also play a role in the triggering or worsening immune-mediated GN such as IgAN and IgAVN. Non-orthostatic proteinuria and/or glomerular hematuria might be associated with the presence of glomerulopathy in patients with NCS or vice versa. Nonetheless, our study has some limitations. First, a small sample size might be not enough to prove the causal relationship between NCS and GN. Studies including multi-centers and large-sized participants are needed to clarify the influence of NCS on the triggering and progression of GN. Second, renal venography with direct pressure measurements was not done in our patients due to its invasive nature. However, NCS was confirmed repeatedly with Doppler US, CT, or MRI in our cases. Third, kidney biopsies of patients were done on their left side except for one patient. While NCP could lead to decreased renal blood flow and histologic changes in the congested left kidney only at first, histopathologic changes would take place in the right kidney as well with time. As a way to support this, we confirmed renal histologic changes of MGAs of the right kidney in one patient (case 7).
In conclusion, NCS may be associated with the presence of various GN. The causal relationship of NCS and GN should be further investigated. We may assume that NCS combined with GN is not rare. Its prevalence could be higher than previously thought. Kidney biopsy should be performed without hesitation to confirm the coexistence of GN with NCS. Inversely, NCS evaluation could be considered in patients with atypical and uncommon courses of various GN.
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