In the Clinic

If you are like many practicing physicians, you probably have a stack of unread journals accumulating dust somewhere in your home or office. You have not tossed them in the recycle bin yet because you remain optimistic that someday you will have a few free minutes to look through them. You also have this nagging sense that there probably is something buried in the stack that you should know. As editors, we would like to believe that our readers rush to read every issue of Annals of Internal Medicine from cover to cover. As clinicians, we know that the realities of practice and life make that unlikely. We also know that, when practicing physicians do get to their journals, they too often find the content irrelevant or, at best, tangential to their daily work of caring for patients. In this issue of Annals, we launch a new section, In the Clinic, to better connect Annals to clinical practice. Funded solely by the American College of Physicians, In the Clinic will appear monthly and will focus on a single, common clinical condition relevant to internal medicine practice. Type 2 diabetes is the inaugural topic of the new section, which you will find on the red-edged pages that follow the journal's usual content. Future topics will cover such issues as preventive care, symptoms, acute conditions, and chronic illness. The foundation for In the Clinic is the evidence-based content of PIER (Physicians' Information and Education Resource). PIER (pier.acponline.org) is a compendium of evidence-based clinical guidance presented in a unique telegraphic format designed for rapid access to clinical information at the point of care. Features include a flow-diagram approach to undifferentiated clinical problems, a quality measurement tool, extensive links to other material useful to practice, and a comprehensive drug resource. PIER draws on all available evidence but rates its guidance and cited literature by evidence level. The content is rigorously peer-reviewed and continually updated. In developing In the Clinic, we also draw on other ACP resources, such as MKSAP (Medical Knowledge Self-Assessment Program), as well as outside resources, including practice guidelines and accepted quality-of-care measures. In the Clinic purposefully and concisely covers very broad topics and emphasizes knowledge that can readily be integrated into practice. Readers who desire greater detail can find it in the source materials and evidence links in PIER. In addition to addressing diagnosis and management, In the Clinic will cover practice improvement and incorporate tools to help physicians to better care for patients with common yet demanding clinical conditions. We think that advice about practice improvement will become increasingly critical to American physicians when improving the quality of care gains momentum. Annals subscribers can obtain 1.5 category 1 continuing medical education (CME) credits by completing the questions on the final page of each issue of In the Clinic. The editors have drawn the questions primarily from MKSAP and have retained the detailed explanations that characterize MKSAP as the preferred self-assessment program for internists. Although nearly all other material in Annals is unsolicited and prepared by independent authors, the editors of In the Clinic will carefully plan, closely direct, and faithfully participate in writing the section to ensure that it aligns with the evidence-based material from which it is derived. In the Clinic is not the usual traditional fare for a high-impact scientific medical journal. The lifeblood of Annals has been (and will continue to be) rigorous original research, scholarly reviews, authoritative practice guidelines, and insightful commentary. However, our readers have been sending clear signals that traditional content may not be doing enough to help them keep up-to-date with the core knowledge necessary to take good care of their patients. Thus, we venture to add this new material to our trusted traditional mix. We are optimistic. Generalists who evaluated a prototype of In the Clinic believed that the section promises to be an effective mechanism for refreshing their knowledge in core clinical topics. Subspecialist physicians found it a painless way to get updates on clinical conditions outside their area of expertise. This section is a value-added feature for those individuals who have their own subscription to Annals. All print copies of Annals will include the new section, but only physicians with their own Annals subscription will have free access to the electronic version (www.annals.org/intheclinic), including links to related PIER modules, references, clinical tools, and the complete CME quiz. We encourage readers who are unfamiliar with PIER to explore this unique clinical information resource, which outranked a dozen other point-of-care evidence-based medicine tools in a recent study performed by the Medical Library Association (Personal communication). Please turn to the red-edged pages and take a look; then tell us what you think.


Background
Postinfection as an etiology for glomerulonephritis (GN) is rarely described in post-transplant recipients and may be due to impaired immune response. It is also possible that such cases are not biopsied or not reported. There are rare case reports in the literature [1][2][3]. We report here a rare first case of Enterococcus-related postinfectious GN in a transplant recipient seen in our center.

Case report
A 64-year-old Caucasian man with past medical history of diabetes and hypertension on hemodialysis for 12 years underwent deceased donor kidney transplant. He underwent induction with Thymoglobulin ® , early steroid withdrawal, and was maintained on tacrolimus and mycophonelic acid. Early post-transplant course was uncomplicated and serum creatinine improved to 1.6 mg/dL (141 µmol/L) by Day 8. He was discharged with an indwelling urinary catheter due to urinary retention which was removed 2 days after discharge and had to be reinserted on Day 12 due to retention. On Day 23, he had a fever and was found to have vancomycin-resistant Enterococcus (VRE) urinary tract infection (UTI) which was treated with meropenem for 10 days. On Day 58, he was found to have an elevated creatinine of 2.4 mg/dL (212 µmol/L), and recurrent VRE UTI. Despite treatment of the UTI and clinical improvement, the graft function continued to deteriorate and creatinine peaked at 4.1 mg/dL (362 µmol/L). He had 0.5 g of proteinuria. Urinalysis showed 53 white blood cells ( WBCs) and >182 red blood cells (RBCs), with many dysmorphic RBCs, but no evidence of tubular casts. Donor-specific antibodies were negative.
Despite antibiotics, intravenous fluids and reduction of immunosuppression, there was no improvement in renal function, and WBCs and RBCs in urine. A transplant kidney biopsy was performed, which showed hypercellular glomeruli with mesangial and capillary loop infiltration of mononuclear cells as well as neutrophils and eosinophils, along with borderline tubulitis (Banff borderline), acute tubular damage and mild isometric vacuolization of the cytoplasm. Crescents were not noted, but there was a minor duplication of the glomerular basement membranes (Figure 1). C4d and BK virus stains were negative. Electron microscopy showed subendothelial and mesangial electron-dense deposits ( Figure 2). Immunofluorescence showed antibodies to IgG (2-3+), IgM (2+), C3 (4+), C1q (2-3+), kappa (2-3+) and lambda (trace to 1+) granular mesangial and capillary loop staining. Antibodies to fibrinogen, IgA and albumin were negative. Complement C3 and C4 were low at 26 mg/dL (reference range 65-180 mg/dL) and 10 mg/dL (reference range 13-52 mg/dL), respectively, with negative ANCA and ANA. The tacrolimus levels were not elevated at any time as to be concerned about toxicity. Cardiac echocardiogram was negative for any vegetation and blood cultures were persistently negative. Findings were most consistent with postinfectious GN in the setting of UTI. He was given methylprednisone 500 mg daily in three doses and did require one session of hemodialysis for volume overload. Oral prednisone was resumed after he had completed his antibiotic therapy, and then discharged on a steroid taper over 10 days. He continued to have repeated episodes of UTI requiring antibiotics with creatinine stabilizing at 2.7 mg/dL (238 µmol/L). Due to persistent urinary retention seen on urodynamics, he underwent ileal loop diversion to the transplanted kidney 2.5 months post-transplant. Following the procedure, his creatinine improved to 1.5 mg/dL (132 µmol/L) and is currently, at 19 months post-transplant, 1.2 (106 µmol/L) with 0.32 g of proteinuria.

Discussion
Postinfectious GN is the most common cause of acute nephritis in children in developing countries. It is more frequent and severe in nontransplant immunocompromised patients such as elderly, HIV, malignancy, alcoholic liver cirrhosis, diabetes or obstructive lung disease. However, despite the high rate of infections in post-transplant patients, it is rarely reported post-transplant. Infections are the most common reason for admissions early post kidney transplant. In one case series, only 3 of 827 patients developed postinfectious GN even though 65% of the patients developed at least one significant bacterial infection during follow-up [1]. Long-term outcome was poor as two of the three patients subsequently lost their graft. The reported 11 cases of transplant biopsy-proven postinfectious secondary GN have been due Staphylococcus aureus sepsis, Staphylococcus urosepsis, post-pharyngitis streptococcal GN, cytomegalovirus infections and Salmonella enteritidis, with variable outcomes.
The pattern of the postinfectious GN seems to be changing in the general population and is no longer associated with only streptococcus or staphylococcal infections. The major pathogenetic mechanism is in situ immune complex formation due to deposition of nephritogenic antigens within the glomerulus. An alternative hypothesis is glomerular trapping of circulating immune complexes. Immunosuppressive agents previously initiated for prevention of rejection should theoretically interfere with the immune response to the infectious agent and prevent the formation of immune complexes. Our case shows the course of VRE-associated postinfectious GN in a transplant patient, which has not been previously described. There is no established therapy for treatment of acute postinfectious GN in these cases aside from aggressive treatment of infection with the appropriate antibiotics to remove the antigenic stimulation. The role of steroids in the treatment of postinfectious GN in these cases is unclear. Five of the reported 11 cases were treated with pulse steroids. Based on limited cases, some authors suggest a short course of pulse steroids while others disagree arguing that it would predispose to further infections. We felt a short steroid course was beneficial for the anti-inflammatory effect aside from aggressive antibiotic therapy and reversal of any potential inciting events. The long-term prognosis of postinfectious GN is poor even in nontransplanted patients where up to 27% have chronic kidney disease and 10% end up on dialysis at 7.5 years of follow-up. To date, there are only three cases of Enterococcus-related GN in native kidneys, of which two were crescentic GN and one membranous [4,5]. To date, there are no cases of Enterococcus-related GN in transplant recipients.
In conclusion, we report the first case of Enterococcusrelated postinfectious GN in a transplant recipient on immunosuppression. These cases are generally associated with extremely poor long-term outcome of graft function. However, with early detection, antibiotics and surgical intervention, sustained long-term renal function is possible.
Conflict of interest statement. The results of this case have not been published previously elsewhere. The authors of this manuscript have no related conflicts of interest to disclose.   2. Electron micrograph of a glomerular capillary loop showing subendothelial and paramesangial electron dense deposits (indicated with an asterisk symbol). Early duplication of glomerular basement membranes is present but interrupted (arrows). In the inset image at upper left, an isolated subepithelial electron dense 'hump' deposit is seen in the mesangial notch region. Original magnification of both images was ×9450. PEC, parietal epithelial cell.