Marked reduction of proteinuria after removal of a growth hormone-producing pituitary adenoma in a patient with focal segmental glomerulosclerosis: a case report and literature review

Abstract

Focal segmental glomerulosclerosis is a rare complication of acromegaly. A 74-year-old man was found to have acromegaly features such as enlargement of the forehead, nose, and hands. Laboratory tests showed a urine protein/creatinine ratio of 3.16 g/gCr and serum creatinine of 1.34 mg/dL. The levels of growth hormone and insulin-like growth factor I were markedly elevated, and the growth hormone level was not suppressed after 75 g oral glucose loading. Magnetic resonance imaging revealed a pituitary tumor with a diameter of 1.2 cm. Renal biopsy confirmed the diagnosis of focal segmental glomerulosclerosis. Transsphenoidal resection of the pituitary tumor led to remission of acromegaly and reduction in proteinuria highlighting the causal link between growth hormone overproduction and proteinuria. Treatment of acromegaly may be effective for acromegaly-associated focal segmental glomerulosclerosis.

Introduction

Focal segmental glomerulosclerosis (FSGS) is one of the main causes of chronic kidney disease worldwide, and is characterized by lesions of some glomeruli (i.e., focal) with partial involvement of the glomerular tuft (i.e., segmental). It may clinically present with marked proteinuria and steroid-resistant nephrotic syndrome. FSGS can be classified into primary and secondary forms. While primary FSGS has no known or apparent cause, secondary FSGS is associated with genetic mutations that affect podocyte function, drugs such as interferon, viral infections, unilateral renal dysplasia, or obesity [1–3].

Acromegaly is caused by overproduction of growth hormone (GH) usually from pituitary adenomas, presenting with enlargement of the hands and feet secondary to both bone expansion and soft tissue swelling [4, 5]. Moreover, acromegaly is associated with other serious complications such as cardiovascular diseases, diabetes, hypertension, and cancers, which contributes to increased mortality [4–6]. Although rare, acromegaly has been also reported to cause unique kidney injury [7]. Patients with active acromegaly present with renal hypertrophy and microalbuminuria [8]. To the best of our knowledge, there are very few reports describing secondary FSGS associated with acromegaly [9–13].

Here, we report the successful treatment of proteinuria in a patient with acromegaly-associated FSGS through transsphenoidal resection of a pituitary adenoma and present a literature review of similar reported cases.

Case presentation

A 74-year-old man had a 14-year history of hypertension and surgery for spinal stenosis 9 years ago. Proteinuria was positive for 5 years and serum creatinine was more than 1 mg/dL for 3 years. The patient had no family history of renal or endocrine diseases. He had been treated for hypertension and renal dysfunction by his previous physician for the past 6 months. For hypertension, 80 mg of valsartan, 5 mg of amlodipine, and 1 mg of indapamide were administered and his systolic blood pressure was controlled at 120–140 mmHg. His serum creatinine had remained 1.1–1.3 mg/dL but proteinuria increased from around 1 g/gCr to 4–6 g/gCre. A renal echo demonstrated that the right and left kidneys were sized 105×48 mm and 109×53 mm, with no apparent renal atrophy and hypertrophy. In addition to the increase of proteinuria, acromegaly was suspected due to the presence of distinct facial features and elevated GH levels leading to the referral to our hospital.

On admission, he had a blood pressure of 129/79 mmHg, a heart rate of 85/min, a height of 165.0 cm, and a weight of 63.6 kg. Physical examination revealed frontal bossing and enlargement of the tongue, hands, and feet. Urinalysis showed a urine protein/creatinine ratio of 3.16 g/gCr. Laboratory tests revealed an elevated blood urea nitrogen (27 mg/dL), an elevated serum creatinine (1.34 mg/dL) with low estimated glomerular filtration rate (43 mL/min/1.73 m²), and a normal serum albumin (4.3 g/dL). Laboratory tests also showed marked elevation of serum GH (28.2 ng/mL, normal range: 0–2.47 ng/mL) and insulin-like growth factor-1 (IGF-1, 733 ng/mL; age- and gender-specific normal range: 54–190 ng/mL) levels. The other laboratory findings are presented in Table 1. The GH levels remained elevated after 75 g oral glucose loading, suggestive of GH overproduction (Table 2). Pituitary magnetic resonance imaging revealed a 1.2 cm pituitary tumor classified as Knosp grade 1 (Fig. 1A). These findings were consistent with the diagnosis of acromegaly. No other endocrinopathy except impaired glucose tolerance and acromegaly was detected during hormonal evaluation.

Table 1.

Laboratory findings of the present case

Urinalysis
Dipstick
Protein	3+
Blood	–
Protein	3.16 g/g Cr
Red blood cell	< 4 cells/high-power field
White blood cells	< 4 cells/high-power field
Cast	–
NAG	30.6 IU/g Cr (0–5.6)
β2 microglobulin	192 ug/L (< 150)
Blood counts
White blood cell	5.6 × 103 cells/μL
Red blood cell	4.28 × 106 cells/μL
Hemoglobin	13.1 g/dL
Hematocrit	40.2%
Platelet	197 × 103 platelets/μL
Biochemistry
Blood urea nitrogen	27 mg/dL (8–20)
Creatinine	1.34 mg/dL (0.46–0.79)
eGFR	43 mL/min/1.73 m2
AST	24 U/L (13–30)
ALT	16 U/L (7–23)
Uric acid	6.0 mg/dL (2.6–5.5)
Total protein	7.4 g/dL (6.6–8.1)
Albumin	4.3 g/dL (3.7–5.4)
Total cholesterol	216 mg/dL (0–219)
Triglycerides	189 mg/dL (0–149)
Glucose	93 mg/dL (70–109)
HbA1c	5.7% (4.6–6.2)
C-reactive protein	0.03 mg/dL (0–0.14)
IgG	1454 mg/dL (861–1747)
IgG4	24 mg/dL (11–121)
IgA	252 mg/dL (93–393)
IgM	82 mg/dL (50–269)
C3	80 mg/dL (73–138)
C4	22.8 mg/dL (11–31)
CH50	49.0 U/mL (31.6–57.6)
Anti-nuclear antibody	160× (0–80)
Homogeneous	Positive
Speckled	Positive
Anti-dsDNA antibody	2.2 IU/mL (0–12.0)
MPO-ANCA	< 1.0 U/mL
PR3- ANCA	< 1.0 U/mL
Endocrinology
GH	28.2 ng/mL (0–2.47)
IGF-1	733 ng/mL (54–190)
ACTH	80.9 pg/mL (7.2–63.3)
Cortisol (baseline)	23.0 μg/dL (7.07–19.6)
Cortisol at 1 mg DST	1.6 μg/dL (< 1.8)
TSH	1.05 μIU/mL (0.5–5.0)
FT3	2.49 pg/mL (2.3–4.0)
FT4	1.50 ng/dL (0.9–1.7)
PRL	7.70 ng/mL (3.7–16.3)
LH	3.10 mIU/mL (2.2–8.4)
FSH	9.11 mIU/mL (1.8–12.0)
Total testosterone	257 ng/dL (131–871)
whole PTH	57.7 pg/mL (8.3–38.7)
Viral infection
HBs antigen	Negative
HBs antibody	Negative
HCV antibody	Negative
HIV antibody	Negative

Parentheses indicate reference values

NAG N-acetyl-β-D-glucosaminidase, eGFR estimated glomerular filtration rate, AST aspartate transaminase, ALT alanine transaminase, CH50 total complement activity, anti-dsDNA anti-double stranded deoxyribonucleic acid, MPO-ANCA myeloperoxidase-antineutrophil cytoplasmic antibody, PR3-ANCA proteinase 3- antineutrophil cytoplasmic antibody, GH growth hormone, IGF-1 insulin-like growth factor-1, ACTH adrenocorticotropic hormone, DST dexamethasone suppression test, TSH thyroid-stimulating hormone, FT3 free triiodothyronine, FT4 free thyroxine, LH luteinizing hormone, FSH follicle-stimulating hormone, PRL prolactin, PTH parathyroid hormone, HBs hepatitis B surface, HCV hepatitis C virus, HIV human immunodeficiency virus

Table 2.

Preoperative and postoperative growth hormone suppression test results

Time after 75 g glucose loading (minute)	Baseline	30	60	90	120
At diagnosis
Growth hormone (ng/mL)	34.2	32.1	33.2	31.5	28.7
Glucose (mg/dL)	91	161	192	206	154
Three months after surgery
Growth hormone (ng/mL)	2.29	1.1	0.63	0.42	0.32
Glucose (mg/dL)	94	153	191	174	171

Fig. 1.

Pre- and postoperative findings of pituitary magnetic resonance imaging (MRI). A A preoperative T1-weighted image with contrast enhance. This image shows a 12 mm pituitary tumor as a less enhancing lesion (white arrow). The normal pituitary gland is shoved to the upper left of the sella turcica. B A postoperative T1-weighted image without contrast. After tumor resection (white arrow), the normal pituitary gland is decompressed

Among the 26 glomeruli retrieved via percutaneous renal biopsy, histopathologic findings include global sclerosis in 6 glomeruli, segmental sclerosis in 3 glomeruli, and adhesion in 2 glomeruli. Others exhibited glomerular hypertrophy (the maximum diameter; 250 μm) with mild mesangial cell proliferation. Moreover, tubular atrophy with interstitial fibrosis and inflammatory cell infiltration was observed in 50% of the renal cortex. Arteriolar wall thickening was also identified (Fig. 2). Immunostaining for immunoglobulins and complement proteins showed negative or non-specific deposition. Electron microscopy revealed the foot process effacement of podocytes and widening of the subendothelial spaces (Fig. 3). These findings were consistent with a diagnosis of FSGS, not otherwise specified.

Fig. 2.

Histopathologic examination of the renal biopsy specimen. Periodic acid-Schiff staining of the renal biopsy specimen reveals focal segmental glomerulosclerosis (arrowheads). Original magnification: A 100 × and B 200 × 

Fig. 3.

The findings of electron microscopy. The foot process effacement of podocytes (arrowheads) is observed in electron microscopy study. Scale bar indicates 5 µm

The pituitary tumor was completely removed by transsphenoidal surgery, confirmed by magnetic resonance imaging (Fig. 1B). Based on histopathological analysis, the tumor was diagnosed with a GH-producing adenoma (Fig. 4).

Fig. 4.

Histopathological findings of the resected pituitary tumor. Staining images of hematoxylin and eosin (A), growth hormone (B), CAM5.2 (C) and MIB-1 (D). The tumor cells harbor eosinophilic cytoplasm (A), 40% of which were positive for growth hormone (B). CAM5.2 staining showed a dotted perinuclear pattern in the tumor cells (C). MIB-1 labeling index was calculated as 0.6% (D). Scale bars indicate 50 µm

A 1-month follow-up showed improvement of the urinary protein/creatinine ratio (0.71 g/gCr) and GH level (6.41 ng/mL). A 3-month follow-up revealed further reduction of the urinary protein/creatinine ratio (0.3 g/gCr) under the same antihypertensive agents as before (blood pressure, 116/77 mmHg). The IGF-1 level was normalized (153 ng/mL). Finally, the GH level after 75 g oral glucose loading decreased to less than 0.4 ng/mL, indicating remission of acromegaly (Table 2). One year after surgery, proteinuria remained at about 0.7–1.0 g/gCr and serum creatinine was 1.53 mg/dL. Valsartan was maintained at 80 mg and no immunosuppressive therapy was used.

Discussion

We encountered a case of massive proteinuria and renal dysfunction in a patient with acromegaly-associated FSGS confirmed via renal biopsy. Treatment with transsphenoidal surgery significantly improved proteinuria and lead to complete remission of acromegaly. These findings suggest a potential association between GH overproduction and glomerular injury in acromegaly.

GH receptor is expressed in glomerular cells such as podocyte and mesangial cells [14, 15]. Since FSGS is a condition associated with podocyte damage [16], the role of GH overproduction in podocyte injury has been demonstrated in a number of studies [7, 17]. One of which showed that GH-transgenic mice presented with glomerular hypertrophy and podocyte injury [18]. Furthermore, several studies have described that GH promotes mesenchymal-to-epithelial transition or apoptosis via Notch signaling or transforming growth factor-beta/Smad signaling pathway in podocytes [19, 20]. IGF-1 receptor is expressed in glomeruli, but overexpression of IGF-1 did not cause obvious glomerulosclerotic lesions [18, 21]. Based on the findings of these basic studies and the course of decreased proteinuria after acromegaly treatment, we speculate that GH overproduction directly causes podocyte injury and FSGS in our patient. There is no family history suggestive of hereditary FSGS, and the absence of a history of FSGS-causing drugs treatment or suspected viral infection such as HIV also supports the association of FSGS and acromegaly in this case. However, one limitation is that acromegaly was diagnosed just prior to referral, so the time of onset and duration of the disease are unknown. Thereby, we cannot accurately compare the onset of renal impairment.

The patient has a long history of hypertension, which can be associated with acromegaly [4, 5]. In addition, atherosclerotic lesions were also observed on the renal biopsy, suggesting the presence of hypertensive renal injury. It is possible that long-term hypertension may have affected renal function and the course of proteinuria in this case.

To the best of our knowledge, there are only six cases of FSGS with associated acromegaly, including the present case [9–13] (Table 3). Among these, all the patients were men with an average age of 58.2 years. The degree of proteinuria was variable with three cases of nephrotic-range proteinuria [9, 11]. In all the cases, treatment with surgery or pharmacologic therapy led to remission of acromegaly. In three cases with severe proteinuria, immunosuppressive therapy (e.g., corticosteroids) was administered [9, 11, 13]. Moreover, five cases received renin–angiotensin–aldosterone system inhibitors [9, 10, 12, 13]. Regarding the renal outcomes, reduction of proteinuria or partial remission of nephrotic syndrome was observed in five cases [9, 11–13].

Table 3.

Summary of FSGS cases in acromegaly patients

Age/sex	Baseline renal function	Treatment	Renal function at final follow-up	References
46/M	sCr 0.8 mg/dL	Corticosteroid	sCr 1.2 mg/dL	[9]
	UP 8.2–15.0 g/day	Immunosuppressants	UP 1.0 g/day
		Surgical treatment
		LDL adsorption
		Somatostatin analogue
		ACEi
53/M	sCr 132 μmol/L	Surgical treatment	UP 2 +	[10]
	UP 3 + ; 1.4 g/day	ACEi
63/M	sCr 130.4 μmol/L	Corticosteroid	sCr 80.0 μmol/L	[11]
		Surgical treatment	UP 2.0 g/day
	UP 9.1 g/day
64/M	cCr 0.6 mg/dL	Surgical treatment	UP 513 mg/day*	[12]
	UP 967.3 mg/day*	ARB
49/M	sCr 61 μmol/L	Corticosteroid	sCr 76 μmol/L	[13]
	UP 6.29 g/day	ARB, TAC, Tripterygium	UP 2.85 g/day
		Surgical treatment
74/M	sCr 1.34 mg/dL	Surgical treatment	sCr 1.53 mg/dL	Present case
	UP 3.16 g/gCr	ARB	UP 0.7–1.0 g/gCr

M male, sCr serum creatinine, UP urinary protein, ACEi angiotensin-converting enzyme inhibitor, ARB angiotensin II receptor blocker, TAC tacrolimus

^*Average of three examinations

Surgical excision of pituitary tumors is a standard therapy for acromegaly. In addition, pharmacologic therapy such as somatostatin analogs or GH receptor antagonists has also been widely used [4, 5]. Reduction of GH and/or IGF-1 is reported to improve cardiovascular comorbidities and mortality in patients with acromegaly [22, 23]. Previous study reported that immunosuppressive therapy improved the proteinuria of a patient with FSGS [13], however, in our case, transsphenoidal surgery was effective in treating acromegaly and reducing proteinuria, avoiding the potential side effects of immunosuppressants. There are some cases with FSGS in which reduction of proteinuria can be expected with surgical therapy alone, but further studies are required to identify the optimal management strategy for renal complications in patients with acromegaly.

In our case, the patient presented with severe tubulointerstitial damage in the absence of a history of treatment with medications known to cause tubular injury (e.g., non-steroidal anti-inflammatory drugs and antimicrobials) [24]. Moreover, other systemic diseases (e.g., IgG4-related disease and sarcoidosis) that could have complicated tubular injury [24] were excluded. Although the cause of tubular injury in the present case is unknown, it might be possible that the GH overproduction contributed to the tubular injury since the expression of GH receptors was demonstrated in renal tubular cells [25]. Furthermore, aged GH-transgenic mice exhibited tubular changes in addition to glomerulosclerosis [18].

We have described a rare case of acromegaly-associated FSGS. This study highlights the utility of surgery in treating acromegaly to improve the clinical outcomes of FSGS.

Declarations

Conflict of interest

The author(s) declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from this patient.