Unusual Urothelial Tumors and Refractory Uremia Due to Balkan Endemic Nephropathy: A Case Report

Abstract

Balkan endemic nephropathy (BEN) is a rare progressive chronic renal disease found in residents living along the Balkan peninsula. We present a 92-year-old female who complained initially of cardio-respiratory symptoms and was found to have an acute hypoxemic respiratory failure with hypervolemia. The patient underwent computed tomography imaging and was found to have bilateral pleural effusions and moderate left-sided renal atrophy with left-sided hydronephrosis. The patient underwent diuresis for fluid overload and was treated with broad-spectrum antibiotics for hospital-acquired pneumonia. Further urological work-up revealed masses in the posterior bladder wall and left ureteropelvic junction. A biopsy of the posterior bladder wall mass confirmed high-grade papillary urothelial carcinoma. A review of the epidemiological history revealed the patient lived in Kosovo/former Yugoslavia for several decades following birth. A review of old records revealed the patient had chronic kidney disease (CKD) that was not fully explained by other causes, such as hypertension or diabetes. Given the epidemiological history, accelerated CKD, and unusual locations of urothelial carcinoma, the patient was diagnosed with BEN. Despite medical management and hemodialysis, the patient’s renal function and mental status continued to deteriorate, and the decision was made to proceed with palliative care measures.

Introduction

Balkan endemic nephropathy (BEN) is a chronic renal tubulointerstitial disease that affects residents of the Balkan states in Southeast Europe, particularly those residing near the Danube River. Balkan endemic nephropathy is rare and has been reported in 0.5% to less than 5% of the population who have been screened for the condition. However, research suggests that the incidence rate would be much higher if intensive screening were performed in high-risk areas. ¹

Long-term, low-level exposure to aristolochic acid, a mutagenic and nephrotoxic alkaloid from the Aristolochia clematitis plant, has been identified as the primary cause of BEN. Accidental ingestion in the form of milled flour contaminated with Aristolochia clematitis seeds has been identified as the primary source of exposure in the region. Unlike the classic presentation of aristolochic acid nephropathy which results in rapid kidney dysfunction in consumers of Chinese herbs and “slimming pills,” BEN is different—it is a slow process, taking 10-20 years for histological changes to present. ²

Genetic predisposition in the form of polygenic inheritance has also been suggested as a possible cause for BEN; however, the evidence supporting this hypothesis is inconsistent. ¹ The effects of BEN typically go unnoticed in the early stages of the disease and begin to manifest around 50 years old in most patients. Physiological changes secondary to BEN begin with clinically silent tubular dysfunction. Following a sustained period of tubular injury, renal glucosuria and aminoaciduria occur, later followed by diminished ability to regulate acids and bases.^1,2

Additionally, there are features in BEN that may help establish the diagnosis. For example, anemia out of proportion to renal dysfunction has been noted. ² In the later stages of BEN, a patient can expect to experience a progressive decrease in glomerular filtration rate (GFR) and urine concentrating ability. This process will eventually result in end-stage renal disease (ESRD) requiring hemodialysis for about one-third of all BEN patients.^{1 -3} A high incidence of transitional cell carcinoma of the renal pelvis, ureter, and bladder is also expected for BEN patients. These masses tend to be superficial in their location and slow-growing.^1,2,4 Nonetheless, there are no established or definitive criteria for the diagnosis of BEN despite earlier proposals to establish such criteria. A combination of epidemiological history (having lived in an endemic area with exposure to aristolochic acid) and sequelae (proteinuria, anemia, renal atrophy, etc.) provides strong evidence to make the diagnosis. ⁵

Case Presentation

A 92-year-old female from Kosovo/former Yugoslavia presented with chest pain, dyspnea, and bilateral lower extremity edema. The patient’s past medical history is significant for multiple issues including stage 4 chronic kidney disease (CKD), type 2 diabetes requiring insulin (IDDM), hypertension (HTN), hyperlipidemia (HLD), coronary artery disease (CAD) status, post-coronary artery bypass graft (2×) (CABG) with 7 stents, myelodysplastic syndrome (MDS) with anemia, and osteoporosis complicated by multiple rib fractures. Her medications include multiple anti-hypertensive agents including clonidine, doxazosin, hydralazine, isosorbide mononitrate, and nifedipine in addition to aspirin, furosemide, carvedilol, empagliflozin, and denosumab.

The patient was found to be tachypneic and hypoxemic with SpO2 in the low 90% range. Initial labs were significant for hyponatremia of 121 mmol/L, hyperkalemia of 5.8 mmol/L, creatinine of 2.4 mg/dL elevated from 1.4 mg/dL from 2 days prior, hemoglobin of 13.1 g/dL (12.1 g/dL 2 days prior), troponin of 14 pg/mL which decreased to 13 pg/mL approximately 4 hours later, and brain natriuretic peptide (BNP) of 393 pg/mL. Urinalysis (UA) showed glucosuria (1000 mg/dL), hematuria 52/high-powered field, white blood cell (WBC) >900/high-powered field, leukocyte esterase 500, and proteinuria 70 mg/dL. All lab data are included in Table 1.

Table 1.

Lab Values Including Reference Ranges. Time Starts at Presentation (0 Hours), and Additional Columns Represent Time After Presentation. Selected Data at Pertinent Time Points Are Shown. Labs Were Drawn in the Morning Hours Between 0400 and 0600, Except on Day 1 When the Labs Were Drawn at Approximately 0800. Dialysis Times are Listed in 24-Hour Time Format and are Highlighted in Yellow in the Top Row.

Laboratory test results	Reference range	t = day 1	t = day 2	t = day 3	t = day 4	t = day 5	t = day 6	t = day 7	t = day 8	t = day 9	t = day 10	t = day 11
DIALYSIS time									1500-1900	1000-1400	1300-1700	0900-1200
WBC K/µL	3.8-10.8	8.8
Hemoglobin g/dL	14-18	13.1
Platelet count K/µL	150-450	171
Sodium mmol/L	136-145	121	128	134	130	128	128	128	130	136	138	142
Potassium mmol/L	3.6-5.1	5.8	5.6	4.3	4.3	4.3	4.3	4.4	4.6	4	4.1	3.8
Calcium mg/dL	8.6-10.3	8.8	8.4	8.4	8.2	8.3	8.2	8.7	8	7.8	7.5	8.2
Magnesium mg/dL	1.5-2.5	2.1
Phosphorus mg/dL	2.5-5.0		4	3.6	2.8	3.3	4	5.1	6	4.3	4.1	2.2
HCO3- mmol/L	23-29	18.6	23.1	22.8	25.9	23.4	24.1	23.4	22.9	28.2	26	27.5
Anion gap	4	10	7	13	6	9	9	10	11	12	13	13
Glucose mg/dL	70-105	171	132	129	200	155	209	174	213	131	252	244
Blood urea nitrogen mg/dL	7-25	49	48	44	49	51	61	70	86	62	63	67
Creatinine mg/dL	0.7-1.3	2.4	2.1	1.8	2.2	2.3	2.7	2.9	3.5	2.7	2.7	2.7
BUN/creatinine ratio		20.4	22.9	24.4	22.3	22.2	22.6	24.1	24.6	23	23.3	24.8
Osmolality calculated mOsm/kg		261	268	281	279	274	280	282	293	291	302	311
Osmolality measured mOsm/kg	270-295	280
eGFR mL/min/1.73 m2	> 60	17.01	19.99	24.09	18.9	17.91	14.75	13.53	10.78	14.75	14.75	14.75
Albumin g/dL	3.5-5.7	3.4
Bilirubin mg/dL	0.1-1.0	0.5
Alkaline phosphatase IU/L	34-104	90
AST IU/L	13-39	25
ALT IU/L	7-52	18
High-sensitivity troponin I pg/mL	< 20	14				55
Brain-natriuretic peptide pg/mL	1-100	393				476
Urinalysis
Color	Yellow	Yellow						Dark brown
Clarity	Clear	Turbid						Turbid
Glucose mg/dL	Negative	1000						200
Bilirubin	Negative	Negative						Negative
Ketones	Negative	Negative						Negative
Specific gravity	1.016-1.022	1.01						1.016
Blood	Negative	1+						3+
pH	5.0-8.0	5.5						5.5
Protein mg/dL	Negative	70						100
Urobilinogen mg/dL	0.2	< 0.2						0.2
Nitrite	Negative	Negative						Negative
Leukocyte esterase	Negative	500						500
RBC/HPF	0-5	52						> 900
WBC/HPF	0-5	> 900						> 900
Bacteria/HPF	Negative	1+						114
Hyaline casts/HPF	0-9	8						Negative
Squamous epithelial cells/LPF		0						0
Yeast budding/HPF	None	Few
Urine sodium mmol/L		61					36
Urine creatinine mg/dL							48.5
Urine nitrogen mg/dL							370
Urine osmolality		257
FeUrea							32.50%

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; FeUrea, fractional excretion of urea; HPF, high power field; LPF, low power field; RBC, red blood cell; WBC, white blood cell.

Computed tomography (CT) chest abdomen pelvis was obtained without contrast given the patient’s acute kidney injury (AKI) showing a dense opacity in the right lower lobe, small bilateral pleural effusions, left kidney moderately atrophic compared with right, moderate left-sided hydronephrosis, and mild bladder wall thickening (as shown in Figure 1). Renal ultrasound showed persistent mild to moderate left-sided hydronephrosis without masses in the urinary tract.

Figure 1.

(A) Computed tomography chest abdo pelvis without contrast obtained in emergency room on day 1 moderate atrophy and hydronephrosis of the left kidney. Possible mass (approximate area indicated by red arrow) causing obstruction is not excluded. (B) Right kidney appears grossly normal.

The patient was initially treated for hospital-acquired pneumonia (HAP) with intravenous (IV) vancomycin and cefepime given her recent 8-day hospitalization for hyperkalemia from which she was discharged just 2 days prior. The patient was also started on diuretics with IV furosemide 40 mg on day 1 in the setting of hypotonic hypervolemic hyponatremia attributed to her AKI.

Urology was consulted on day 2 of hospitalization. The patient underwent cystoscopy, CT urogram, and left ureteropelvic junction (UPJ) dilation with stent placement. Cystoscopy revealed a mass in the left UPJ (stent placed, Figure 2) and a posterior bladder wall mass (resected, Figure 3). Given the unusual tumor locations, the urologist obtained further history from the patient. The patient and her son confirmed that she was born in Kosovo/former Yugoslavia in the Balkan Peninsula and lived there for several decades after birth. Given the tumor location and the patient’s many years spent in the Balkan Peninsula, at this time, the diagnosis of BEN was deemed very likely.

Figure 2.

Computed tomography urogram performed on day 2 showing obstruction in the left ureteropelvic junction.

Figure 3.

Cystoscopy performed on day 2 showing a discrete mass in the posterior bladder wall. This mass was later resected and confirmed as high-grade papillary urothelial carcinoma with high suspicion for early lamina propia invasion.

Given concern for underlying BEN, further history was obtained. The patient noted that her mother suffered from cancer of unknown type at age 46. The patient was not aware of any family or personal history of kidney diseases. She denied smoking history but did report problems with managing her HTN. Per the patient’s son, she would measure her blood pressures multiple times per day which was anxiety provoking resulting in higher readings of systolic blood pressure (SBP) on cyclic checks followed by the need for an as needed dose of clonidine. This cycle would occur frequently throughout the day. The patient’s son also stated that her average SBP was between 100 and 120 mmHg as a result of frequent blood pressure monitoring and utilization of clonidine as needed in addition to scheduled antihypertensives.

During the initial course of hospitalization, the patient had transient episodes of delirium that self-resolved. However, on days 6 and 7, the patient once again developed delirium which was persistent and likely multifactorial in light of metabolic derangements, ongoing infection, and hospitalization. New labs were obtained, including urine creatinine (48.5 mg/dL), urine sodium (36 mmol/L), and urine urea nitrogen (370 mg/dL) to calculate FeUrea of 32.5%, suggesting a prerenal etiology. Initial urine culture from day 1 (resulted day 4) grew Candida tropicalis with 50-100×10³ colony forming units/mL. Urine culture from the renal pelvis also later grew the same organism. Given worsening clinical status and worsening creatinine, IV fluconazole was initiated for treatment of complicated fungal urinary tract infection. Notably, the patient did have an in-dwelling urinary catheter during her previous 8-day hospital admission for hyperkalemia and had another in-dwelling urinary catheter placed on day 1 of this admission. The patient also completed a 7-day course of IV vancomycin and cefepime for HAP.

It was noted that the patient’s creatinine (Table 1) initially improved from 2.4 to 1.8 mg/dL by day 3, only to plateau around 2.2 mg/dL, and then began to worsen again by day 6. The diuretic doses were reviewed and were as follows: IV furosemide 40 mg (day 2), 20 mg (day 3), and 60 mg (day 4). No diuretics were given on days 5 and 6, but IV bumetanide 3 mg was given on day 7.

Urine cytology collected on day 2 (resulted on day 7) showed rare atypical cells favoring a reactive process without overt evidence of malignancy. Biopsy of the posterior bladder wall mass on day 4 (resulted on day 8) confirmed high-grade papillary urothelial carcinoma with high suspicion for early lamina propria invasion. Thus, the definitive diagnosis of BEN was made.

On day 7, nephrology was consulted for hypervolemia and uremia refractory to ongoing medical management. Hemodialysis with ultrafiltration was performed on days 8-11 (4 total sessions of hemodialysis with ultrafiltration), as seen in Table 1. Over days 8-11 though, the patient’s delirium continued to worsen further. On day 11, while the patient was undergoing the fourth round of hemodialysis, she became hypotensive and hypoxemic, so dialysis was stopped and supplemental oxygen via non-rebreather mask was started. End-of-life discussions were held with the patient's family and the decision was made to pursue comfort care measures. The patient passed away shortly after comfort care was initiated.

Discussion

Given our patient’s progression to ESRD, tumors in the UPJ and posterior bladder noted on cystoscopy, urine findings of glucosuria and proteinuria, renal atrophy, and a strongly suggestive epidemiological history with decades spent in the Balkan regions, a diagnosis of BEN was considered and eventually made using the available evidence that strongly supported the diagnosis.^1,5

The work-up for this patient included obtaining general labs with complete blood count (CBC) and comprehensive metabolic panel (CMP) to characterize renal dysfunction and underlying blood abnormalities, characterization of urine with UA, imaging with CT and US modalities to highlight renal anatomy, and cystoscopy with biopsy to identify underlying histology of masses. The diagnosis of BEN involves identifying markers in the blood work, urine, imaging, and social history to identify exposures which increase the likelihood of identifying this diagnosis.^{1,4 -6} Serum biomarkers, however, are non-specific and include anemia, glucosuria, and proteinuria, all found in our patient and in a number patients with CKD attributed to other more common causes like diabetes. ¹ The diagnosis of BEN was notably considered after cystoscopy identified masses in the bladder and UPJ, which is classically associated with late-stage BEN.^2,4 Another non-specific finding in our patient was chronic anemia, which can be found in the early part of BEN, ⁷ though our patient did also have concomitant MDS, which confounds this as a diagnostic factor. To rule out other causes of anemia, the patient had completed a colonoscopy in July of 2022 which showed non-bleeding internal hemorrhoids. Additionally, the patient’s CT abdo pelvis imaging (also seen in previous CT imaging) did also show atrophic kidneys L>R which is consistent with BEN. ⁶

In our patient, the differential diagnosis for renal dysfunction was wide and included more common causes such as progression of diabetic nephropathy given the patient’s longstanding history of type 2 diabetes (hemoglobin A1c trend in Figure 4), hypertensive nephropathy (well-controlled blood pressure trend in Figure 5), cardiorenal disease in light of the patient’s elevated BNP with hypervolemia and respiratory dysfunction at hospital arrival, and obstructive uropathy with hydronephrosis due to UPJ and posterior bladder masses leading to acute tubular necrosis (ATN).

Figure 4.

Hemoglobin A1c over time (96 months, 8 years). Average hemoglobin A1c was calculated to be 7.4%.

Figure 5.

Blood pressure over time (approximately 35 months, 3 years) obtained at the patient’s routine hematology-oncology outpatient office visits. Average blood pressure was calculated to be 125/55 mmHg.

The patient was initially treated with fluid restriction and intermittent diuresis as needed for hypervolemia resulting in an initial improvement of renal function. However, unfortunately, diuresis became less effective, necessitating hemodialysis. Eventually though the patient became hypotensive and hypoxemic, and the family decided to withdraw care and the patient passed shortly after.

A literature search reveals that while there are some studies about epidemiological characteristics or proposed biomarkers/metabolic changes,^8,9 there is only 1 clinical case report about a patient with BEN referred post-mortem for autopsy. ¹⁰ This was a 34-year-old male who presented with anemia, HTN, and uremia—similar co-morbidities found in our patient’s presentation (though our patient did have concomitant MDS); he eventually had an arterio-venous fistula and for routine hemodialysis but unfortunately developed progressively worsening HTN and recurrent thrombotic events of the fistula. The patient then had a hospital admission for planned removal of the thrombotic fistula, and due to an inability to undergo appropriate hemodialysis, the uremia and anemia worsened and the patient passed away at age 41. The renal biopsy of the patient in this case report in particular revealed urothelial atypia, which was found in our patient as urothelial carcinoma of the bladder wall (as confirmed in biopsy) and another site of likely urothelial carcinoma in the left UPJ (this site was not biopsied, but was stented). Interestingly, while the patient in the case report seems to have undergone 7 years of hemodialysis, ¹⁰ our patient did not have any hemodialysis until the last 4 days of hospital admission in which shortly after she passed away from likely refractory fluid overload and hypoxemia/hypotension.

We present this case to demonstrate a rare entity of CKD that can only be elucidated by a very careful social and epidemiological history, and that unfortunately, with prolonged disease, there is a real chance of late-stage ESRD and tumorigenesis refractory to aggressive medical management.^1-3 As seen in 1 other case report though, ¹⁰ it does appear that hemodialysis is an option for those that do go on to develop ESRD, provided that they are diagnosed in a timely fashion.