Ketogenic-Diet Shake Containing Uncaria tomentosa-Associated Acute Interstitial Nephritis

Abstract

Uncaria tomentosa is a plant that has been used in traditional medicine for its anti-inflammatory, immunomodulatory, and immunostimulant properties. As a result, it can be found in several over-the-counter supplements worldwide. Acute interstitial nephritis (AIN) can be due to an offending medication, infection, or autoimmunity. We present a case of a patient who was on a strict ketogenic diet, utilizing over-the-counter diet shakes containing the herbal supplement Uncaria tomentosa who developed acute kidney injury with a serum creatinine of 3.6 mg/dL up from a baseline of 0.7 mg/dL. Serological evaluation was negative, and kidney biopsy revealed interstitial inflammatory infiltrates including focally prominent eosinophils and multifocal tubulitis. Stopping the keto-diet shake containing Uncaria tomentosa and concomitant corticosteroid therapy resulted in improvement in kidney function to near baseline. To our knowledge, this is the only biopsy-proven case of AIN in the setting of Uncaria tomentosa use.

Background/Introduction

Uncaria tomentosa, also known as “cat's claw,” is a plant indigenous to the Amazon rainforest. Its hook-like thorns resembling a cat's claw have been used as traditional medicine in South American countries for its purported anti-inflammatory, immunomodulatory, and immunostimulant properties [1]. Its use has been investigated for anti-cancer [2], anti-arthritic [3], and even mouse models of acute ischemic injury [4]. As a result, it can be found in several over-the-counter supplements worldwide. Despite their widespread availability, safety data are lacking, and their effects on the kidney are not well known.

Acute interstitial nephritis (AIN) is a cellular inflammatory process of the kidney interstitium causing kidney dysfunction. AIN can occur in the setting of an offending medication/agent, infection, or autoimmunity. Urinary sediment may show white blood cells (WBCs), WBC casts, and rarely micro-hematuria [5]. On kidney biopsy, light microscopy findings include a cellular infiltrate of the interstitium accompanied by tubulitis and rarely eosinophils or plasma cells [6]. We present a case of a patient who was on a strict ketogenic diet, utilizing over-the-counter diet shakes containing the herbal supplement Uncaria tomentosa who developed acute kidney injury (AKI) and was found to have biopsy-proven AIN. Stopping the keto-diet shake containing Uncaria tomentosa and concomitant corticosteroid therapy resulted in improvement in kidney function to near baseline. To our knowledge, there is only one other case in the literature describing (AKI) in the setting of Uncaria tomentosa use [7].

Case Presentation

A 51-year-old female with a history of papillary thyroid cancer status post-thyroidectomy on levothyroxine, invasive ductal carcinoma status post-lumpectomy on tamoxifen, presented to the emergency department with complaints of fatigue, nausea, polyuria, and polydipsia for the past 1 month. At presentation, vital signs were a blood pressure of 127/82 mm Hg and a heart rate of 87 bpm. She was afebrile with oxygen saturation of 100% on room air, and BMI was 32. The physical exam was unremarkable with no evidence of skin rash or edema. On admission, serum creatinine (SCr) was 3.6 mg/dL. One month prior to this, SCr was 1.3 mg/dL (baseline 0.7 mg/dL). This increase was attributed to the consumption of high protein/ketogenic shakes in the previous 3–4 months which she was advised to discontinue. Renal ultrasound was unremarkable. A serological workup included negative hepatitis panel, ANA, ANCA, normal C3/C4, and anti-ENA panel with no evidence of paraproteinemia (Table 1). The serum absolute eosinophil count was normal at 0.36 k/μL, and urinalysis showed 1+ hemoglobin, 0–5 WBCs, 0–3 RBCs, no casts or bacteria, and the protein-creatinine ratio was 0.6 (Table 2).

Table 1.

Key laboratory studies − serum

Assay	Values	Reference range
Hemoglobin, g/dL	10.3	12.0–15.5
WBC, × 109/L	7.60	3.5–10.5
Platelet count, × 109/L	263	150–450
Total protein, g/dL	7.5	6.3–8.2
Sodium	137	135–146 mmol/L
Potassium	4.0	3.5–5.3 mmol/L
Chloride	102	98–110 mmol/L
Bicarbonate	25	20–32 mmol/L
Blood urea nitrogen, mg/dL	25	7–21 mg/dL
Creatinine, mg/dL	3.2	0.6–1.1 mg/dL
Estimated GFR (MDRD), mL/min/1.73 m2	15	>60
Albumin, g/dL	3.8	3.5–5.0 g/dL
Calcium	9.3	8.6–10.4 mg/dL
Anti-nuclear antigen	Negative	Negative
C-ANCA/P-ANCA	Negative	Negative
C3	136	86–166 mg/dL
C4	19	13–46 mg/dL
IgG	1,099	700–1,600 mg/dL
IgA	171	70–400 mg/dL
IgM	141	40–230 mg/dL
Kappa free, serum	63.3	3.30–19.40 mg/L
Lambda free, serum	48.7	5.7–26.3 mg/L
K/L ratio, serum	1.30	0.26–1.65
Serum immunofixation	Negative	Negative

ANCA, antineutrophil cytoplasmic antibody; C, complement; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

Table 2.

Key laboratory studies − urine

Urinalysis	Values	Reference range
Color	Straw	Colorless
Clarity	Cloudy	Clear
Specific gravity	<1.005	1.001–1.035
PH	6.0	5.0–8.0
Protein	Negative	Negative
Glucose	2+	Negative
Blood	N/A	Negative
Ketones	Negative	Negative
Bilirubin	Negative	Negative
Hemoglobin/blood	1+	Negative
Urobilinogen	Negative	Negative
Leukest	Negative	Negative
Nitrites	Negative	Negative
WBC	0–5/HPF	0–5/HPF
RBC	0–3/HPF	0–3/HPF
Protein/creatinine ratio	0.6	<0.2
Albumin/creatinine ratio	70	<30 mg/g
Osmolality	430	50–1,200 mOsm/kg

NA, not applicable; HPF, high power field.

While the serological workup was taking place, she received intravenous fluids of normal saline with modest improvement of creatinine to 2.6 mg/dL. Given negative serologies and minimal improvement over the course of 1 week, a kidney biopsy was performed. This revealed interstitial inflammatory infiltrates including focally prominent eosinophils and multifocal tubulitis (Fig. 1, 2). There was mild interstitial fibrosis along with moderate arteriosclerosis.

Fig. 1.

Biopsy of native left kidney showing interstitial inflammatory infiltrates including multifocal tubulitis (black arrows). Periodic acid-Schiff ×400.

Fig. 2.

Diffuse tubulointerstitial inflammation by a mixed infiltrate including focally prominent eosinophils (black arrows). Hematoxylin and eosin ×600.

Treatment with prednisone 40 mg daily (approximately 0.5 mg/kg) was started with a plan to taper based on the initial response. One month after starting prednisone, and 2 months after stopping the keto-diet shakes, SCr was 1.94 mg/dL. Prednisone was tapered in 10 mg increments every 4 weeks. Three months after discontinuation of the cat's claw supplement, creatinine had decreased to 1.3 mg/dL. One month after being completely tapered off prednisone, SCr remained stable at 1.0 mg/dL (Fig. 3).

Fig. 3.

Trend of kidney function.

Discussion

We present a case of biopsy-proven AIN in a patient who was consuming an over-the-counter shake as part of a keto diet aimed at weight loss. Despite stopping the offending agent 1 month earlier, renal biopsy showed AIN, and corticosteroid treatment resulted in resolution of AKI.

Given negative serological workup, the absence of infection, and no identifiable offending drugs, further review of the keto-diet supplement the patient was taking showed the presence of Uncaria tomentosa. Additional ingredients included B vitamins, amino acids, ketones, and 40% of the daily recommended amount of sodium in one shake. Given the timing of starting her dietary supplementations and presentation with AKI, we suspected this to be the offending agent with the high sodium content likely contributing to her excessive urination, in combination with tubular dysfunction evidenced by low urine osmolality and glycosuria.

As a herbal supplement well known in traditional medicine, the extracts/derivatives from Uncaria tomentosa have been well studied in the literature looking at its anti-inflammatory effects on a wide variety of diseases such as rheumatoid arthritis and ischemic kidney disease, and it has even been found to have anti-apoptotic properties [2, 3, 4]. Given there is some scientific data to support its antioxidant and anti-inflammatory uses, its use has become a common part of the “keto diet,” a modern form of diet in which the body is programmed to utilize fat for ketosis in an effort to lose weight.

A literature search yielded only one other case of AKI in the setting of Uncaria tomentosa use, albeit without a kidney biopsy being performed. Helipo et al. [7] described a patient with a history of systemic lupus erythematosus who was taking cat's claw as a herbal remedy to treat her arthritic pain. She took 1 capsule four times daily and had an increase in SCr to 3.6 mg/dL (from a baseline of 2.0 mg/dL). A clinical diagnosis of acute allergic interstitial nephritis was made based on urine sediment showing WBC casts, with normal complement levels and double-stranded DNA levels significantly lower than prior. Resolution of acute renal failure was observed 1 month after discontinuation of cat's claw with bland urine sediment. The patient had no increase in her prednisone dosage during this time [7]. Our case adds to this finding and provides biopsy evidence of AIN in the setting of Uncaria tomentosa use.

The occurrence of AIN in the setting of an anti-inflammatory agent is not new. In fact, nonsteroidal anti-inflammatory drug-induced AIN is the most common form of this and has been attributed to the shifting of the cyclooxygenase pathway toward leukotriene production. Unlike nonsteroidal anti-inflammatory drugs, cat's claw has not been shown to affect this pathway but can demonstrate some anti-inflammatory effects by decreasing activation of NF-kB [8] and TNF-alpha inhibition [9]. While the exact mechanism for its association with AIN in this case is unknown, the presence of significant eosinophils on kidney biopsy suggests an allergic-type process as one possibility.

Finally, our patient required treatment with corticosteroids as kidney function worsened despite stopping the keto-diet shakes 1 month prior to presentation. This is not uncommon in the natural course of AIN, and a 4–6-month course of prednisone was utilized based on the available literature [10].

Conclusion

Uncaria tomentosa or cat's claw may be associated with AIN. Treatment involves stopping the offending supplement, and corticosteroids may be beneficial for restoring kidney function. Our case highlights the importance of performing a thorough review of the ingredients listed in over-the-counter supplements when caring for patients presenting with abnormal kidney function.

Statement of Ethics

The Institutional Review Board at Cleveland Clinic Florida requires approval only for original research. This retrospective review of patient data did not require IRB approval in accordance with local/national guidelines. However, written informed consent was obtained from the patient for publication of this case report and accompanying images/information.

Conflict of Interest

The authors state no conflicts of interest. This case was previously presented in abstract form at the American College of Physicians, Florida Chapter Meeting, April 2021.

Funding Sources

No funding was obtained in the preparation of this manuscript.

Author Contributions

Gilda Portalatin and Shane A. Bobart contributed to the design of the study. Gilda Portalatin, Shruti Shettigar, Astrid Carrion-Rodriguez, Sushma Medikayala, Leal Herlitz, Dianne Sandy, Surafel Gebreselassie, and Shane A. Bobart contributed to the analysis of the results, to the writing of the manuscript, and have read and approved the manuscript. Leal Herlitz obtained pathology data. Each author contributed important intellectual content during manuscript drafting or revision, accepts personal accountability for the author's contributions, and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Funding Statement

No funding was obtained in the preparation of this manuscript.