Right Heart, Wronged Kidneys

Case Presentation

A 44-year-old man with a long history of opioid use disorder was brought to the hospital after being found unconscious at a bus station. He was treated with naloxone and regained consciousness, on which he reported regular and recent intravenous heroin and cocaine use. In addition, he noted 1 week of worsening subjective fevers, chills, weakness, cough with blood-tinged phlegm, and increasing pedal edema. He had no medical history and took no medications. He had been undomiciled since leaving prison a year prior. In the emergency room, his temperature was 39°C, pulse 120 beats per minute, BP 105/55 mm Hg, and oxygen saturation 95% on ambient air. Examination revealed a holosystolic murmur at the left sternal border, clear lungs, needle tracks on arms and legs, and pitting edema of both legs. No rash, splinter hemorrhage, Osler nodes, or Janeway lesions were noted, and fundoscopy did not reveal Roth spots. Bloodwork showed a leukocyte count of 17×10³ cells/μl, hemoglobin 8.4 g/dl, creatinine 0.7 mg/dl, and albumin 2.0 g/dl. Urinalysis had large blood and 2+ protein, with 27 leukocytes/hpf and 50 erythrocytes/hpf. Urine protein-creatinine ratio was 1.9 g/g. Blood cultures grew methicillin-resistant Staphylococcus aureus, and intravenous vancomycin was prescribed. Chest computed tomography with contrast revealed septic-appearing emboli in all lobes (Figure 1A). Echocardiogram revealed thickened tricuspid valve with bulky vegetations resulting in malcoaptation and regurgitation (Figure 1B).

Figure 1.

Selected images from diagnostic testing. (A) Representative slice from computed tomography of the chest showing randomly distributed cavitary nodules compatible with septic emboli (arrowheads). (B) Apical four-chamber view from transthoracic echocardiogram demonstrating bulky tricuspid vegetations. (C) Glomerulus showing mild mesangial hypercellularity, endocapillary hypercellularity, and a cellular crescent (Periodic acid-Schiff, original magnification, ×400). (D) Glomerulus showing large cellular crescent (Jones methenamine silver; original magnification, ×400).

Blood cultures remained persistently positive, and at day 10, he underwent cardiac catheter-guided aspiration thrombectomy to debulk the vegetations. Blood cultures finally cleared 2 days later. Over the subsequent 3 weeks, he remained on intravenous vancomycin, and creatinine rose steadily to 3.02 mg/dl. There was persistent microhematuria and proteinuria, with urine protein-creatinine ratio to 2.2 g/g. Additional workup revealed hepatitis C virus (HCV) infection with very high viral load (11,019,341 IU/ml), negative HIV test, and normal complement C3 and C4 levels. ANCA assays, antinuclear antibody, and rheumatoid factor were negative. The patient was started on sofosbuvir/velpatasvir for HCV.

Question 1A

Which of the following diagnoses is most likely to be responsible for the creatinine rise?

1. Vancomycin-associated cast nephropathy

2. Vasculitis associated with levamisole-adulterated cocaine

3. Immune-complex membranoproliferative glomerulonephritis

4. Necrotizing and crescentic glomerulonephritis

5. Endocarditis-associated renal emboli

The correct answer is D.

The patient developed AKI coincident with tricuspid valve endocarditis, and the history and urine tests suggest a nephritic pattern of injury. This picture is inconsistent with vancomycin-associated cast nephropathy (choice A), a postulated form of vancomycin nephrotoxicity that presents with a tubular pattern of injury and a rapid rise in creatinine over hours to days.¹ Septic emboli to the kidneys (choice E) are common in left-sided endocarditis but would not be expected in right-sided endocarditis such as this patient had, and a careful physical examination revealed no peripheral embolic stigmata. The patient used cocaine, and exposure to cocaine adulterated with levamisole is associated with vasculitis that may involve the kidney (choice B). However, levamisole-associated vasculitis virtually always features cutaneous manifestations and positive ANCA, neither of which the patient had.²

Acute glomerulonephritis associated with bacterial endocarditis seems to be the likely diagnosis. The most common pattern of kidney injury seen with this entity is a necrotizing and crescentic glomerulonephritis with a relative paucity of immunoglobulins^3,4 (choice D). A chronic immune-complex membranoproliferative glomerulonephritis (choice C) may be seen in chronic infections but is not commonly found with endocarditis; in a series of 49 patients with endocarditis-associated glomerulonephritis, none had a membranoproliferative pattern of injury, and only 27% of cases had staining for IgG.³

Case—Continued

With persistently rising creatinine, kidney biopsy was performed on hospital day 37. It revealed pauci-immune acute necrotizing and crescentic glomerulonephritis (Figure 1, C and D). Of 21 glomeruli sampled, three had cellular or fibrocellular segmental crescents and an additional glomerulus had fibrinoid necrosis without a crescent. There was diffuse interstitial edema and tubular degenerative changes. Interstitial fibrosis and tubular atrophy involved approximately 10% of the cortex.

Question 1B

In light of the biopsy findings, which of the following statements is most accurate?

1. Streptococci are the most common organism to cause this pathology.

2. Electron microscopy will probably show subepithelial humps.

3. The pathology is more likely representative of bacterial infection than HCV.

4. A repeated ANCA assay will likely be positive.

5. Control of the infection with appropriate antibiotics will be associated with a favorable outcome.

The correct answer is C.

While this patient was also found to have HCV, the overall pattern of injury seen on the biopsy was much more characteristic of bacterial endocarditis than of viral-associated glomerulonephritis (choice C). HCV most often produces mesangial proliferative or membranoproliferative glomerulonephritis, and it is frequently characterized by circulating hypocomplementemia and mixed cryoglobulinemia (whereas this patient had normal complements and negative rheumatoid factor), as well as a smoldering progression of kidney injury rather than the acute decline seen in this patient.⁵

The most common bacteria to cause endocarditis, including endocarditis associated with glomerulonephritis, are staphylococci, especially S. Aureus^3,4,6 (choice A is incorrect). The pattern of injury associated with these infections forms a distinct subtype of “infection-related glomerulonephritis (IRGN).” The classic subepithelial humps of post-streptococcal glomerulonephritis are relatively uncommon with S. Aureus-associated glomerulonephritis,⁷ and in the aforementioned series of endocarditis-associated glomerulonephritis, humps were only seen in 14%³ (choice B is incorrect). Despite the frequently crescentic and vasculitic appearance of injury on light microscopy, ANCA are positive in only a minority of patients^3,4,8 (choice D is incorrect).

While treatment with antibiotics is fundamental, despite this, the morbidity and mortality of endocarditis-associated glomerulonephritis remain high (choice E is incorrect).^3,4,8,9 Many series suggest a <50% rate of survival with intact kidney function. In the series by Boils et al., 21% of patients died, 10% had end-stage kidney disease, and 37% had persistent kidney dysfunction while only 32% made a full recovery.³ Despite such poor outcomes, the role for additional therapy beyond antibiotics is controversial. While some experts recommend against any use of immunosuppression in the setting of endocarditis,⁷ multiple case reports and series describe positive outcomes after the addition of immunosuppression, chiefly corticosteroids, in select patients.^3,9,10 A recent randomized trial of corticosteroids in IRGN failed to show significant improvement in outcomes, with the caveats that the trial was underpowered and did not include patients with endocarditis.¹¹ It is difficult to extrapolate from such data a clear picture of which patients might benefit from immunosuppression.

Case—Conclusion

Because of persistent worsening kidney function despite clearance of blood cultures and continued antibiotics, and after interdisciplinary discussion with the cardiology and infectious disease consultants, the patient was started on high-dose glucocorticoids. Methylprednisolone 500 mg was given daily for 3 days, followed by prednisone 60 mg daily for 1 week, then tapering. Immediately after glucocorticoid initiation, the creatinine began decreasing. He was discharged on hospital day 51, nearly 2 weeks into the glucocorticoid taper, with a creatinine of 1.22 mg/dl. He did not follow up at a scheduled postdischarge visit with our nephrology clinic, but he was briefly in the emergency department for unrelated reasons 1 month later, and creatinine at that time was stable.

Summary

Glomerulonephritis associated with infective endocarditis is a subtype of IRGN characterized by distinct clinical features and patterns of kidney injury. Despite the frequently crescentic pathology, ANCA are only detected in a minority of patients. Outcomes are generally poor; the role of additional immunosuppression remains undefined but may be considered in select cases who worsen despite appropriate infection control.

Disclosures

P.A. Canetta reports consultancy for Chinook, Novartis, Otsuka, and Travere and research funding from Calliditas, Novartis, and Travere.

Funding

None.

Author Contributions

Conceptualization: Pietro A. Canetta.

Writing – original draft: Pietro A. Canetta.

Writing – review & editing: Pietro A. Canetta.