Isabelle Ayoub

Revisiting medullary tophi: a link between uric acid and progressive chronic kidney disease?

BACKGROUND It is well-established from autopsy studies that gouty tophi can form in the kidney, particularly in the renal medulla. Recently hyperuricemia has been identified as a risk factor for progression of chronic kidney disease (CKD). Because each collecting duct serves more than 2,000 nephrons, we postulated that obstruction or disruption of collecting ducts by medullary tophi may explain, at least in part, the association between hyperuricemia and progressive CKD. This work was done to determine the prevalence of medullary tophi in CKD patients. METHODS We queried our nephropathology database over the last 10 years for native kidney biopsies that had medullary tophi. The presence or absence of CKD and uric acid levels around the time of biopsy were determined by chart review. RESULTS Predominant medullary tissue was reported in 796 of 7,409 total biopsies, and 572 of these were from patients with established CKD. Medullary tophi were seen in 36 patients, 35 of whom had CKD, suggesting a minimum prevalence of tophi in CKD and no-CKD of 6.11 and 0.45%, respectively Medullary tophi occurred with and without hyperuricemia or a history of gout. CONCLUSION Medullary tophi appear to be far more likely to occur in CKD compared to no-CKD patients. This cross-sectional study cannot determine whether medullary tophi are a cause or consequence of CKD. However, given their location and bulk, it is possible that medullary tophi contribute to progression of established CKD by causing upstream nephron damage.

Colon Necrosis Due to Sodium Polystyrene Sulfonate with and without Sorbitol: An Experimental Study in Rats.

Introduction Based on a single rat study by Lillemoe et al, the consensus has been formed to implicate sorbitol rather than sodium polystyrene sulfonate (SPS) as the culprit for colon necrosis in humans treated with SPS and sorbitol. We tested the hypothesis that colon necrosis by sorbitol in the experiment was due to the high osmolality and volume of sorbitol rather than its chemical nature. Methods 26 rats underwent 5/6 nephrectomy. They were divided into 6 groups and given enema solutions under anesthesia (normal saline, 33% sorbitol, 33% mannitol, SPS in 33% sorbitol, SPS in normal saline, and SPS in distilled water). They were sacrificed after 48 hours of enema administration or earlier if they were very sick. The gross appearance of the colon was visually inspected, and then sliced colon tissues were examined under light microscopy. Results 1 rat from the sorbitol and 1 from the mannitol group had foci of ischemic colonic changes. The rats receiving SPS enema, in sorbitol, normal saline, distilled water, had crystal deposition with colonic necrosis and mucosal erosion. All the rats not given SPS survived until sacrificed at 48 h whereas 11 of 13 rats that received SPS in sorbitol, normal saline or distilled water died or were clearly dying and sacrificed sooner. There was no difference between sorbitol and mannitol when given without SPS. Conclusions In a surgical uremic rat model, SPS enema given alone or with sorbitol or mannitol seemed to cause colon necrosis and high mortality rate, whereas 33% sorbitol without SPS did not.

Acute glomerulonephritis with large confluent IgA-dominant deposits associated with liver cirrhosis

Background Small glomerular IgA deposits have been reported in patients with liver cirrhosis, mainly as an incidental finding in autopsy studies. We recently encountered nine cirrhotic patients who presented with acute proliferative glomerulonephritis with unusually large, exuberant glomerular immune complex deposits, in the absence of systemic lupus erythematosus (SLE) or monoclonal gammopathy-related kidney disease. Deposits were typically IgA dominant/codominant. Our aim was to further elucidate the etiology, diagnostic pitfalls, and clinical outcomes. Methods We present clinical features and kidney biopsy findings of nine cirrhotic patients with an unusual acute immune complex glomerulonephritis. We also identified native kidney biopsies from all patients with liver cirrhosis at our institution over a 13-year period (January 2004 to December 2016) to evaluate presence of glomerular IgA deposits in them (n = 118). Results Six of nine cirrhotic patients with the large immune deposits had a recent/concurrent acute bacterial infection, prompting a diagnosis of infection-associated glomerulonephritis and treatment with antibiotics. In the remaining three patients, no infection was identified and corticosteroids were initiated. Three of nine patients recovered kidney function (one recovered kidney function after liver transplant); three patients developed chronic kidney disease but remained off dialysis; two patients became dialysis-dependent and one patient developed sepsis and expired shortly after biopsy. Within the total cohort of 118 patients with cirrhosis, 67 others also showed IgA deposits, albeit small; and 42 patients had no IgA deposits. Conclusions These cases provide support to the theory that liver dysfunction may compromise clearance of circulating immune complexes, enabling deposition in the kidney. At least in a subset of cirrhotic patients, a superimposed bacterial infection may serve as a “second-hit” and lead to acute glomerulonephritis with exuberant immune complex deposits. Therefore, a trial of antibiotics is recommended and caution is advised before immunosuppressive treatment is offered. Unfortunately, most of these patients have advanced liver failure; therefore both diagnosis and management remain a challenge.

Immune gene expression in kidney biopsies of lupus nephritis patients at diagnosis and at renal flare

Background Up to 50% of lupus nephritis (LN) patients experience renal flares after their initial episode of LN. These flares contribute to poor renal outcomes. We postulated that intrarenal immune gene expression is different in flares compared with de novo LN, and conducted these studies to test this hypothesis. Methods Glomerular and tubulointerstitial immune gene expression was evaluated in 14 patients who had a kidney biopsy to diagnose LN and another biopsy at their first LN flare. Ten healthy living kidney donors were included as controls. RNA was extracted from laser microdissected formalin-fixed paraffin-embedded kidney biopsies. Gene expression was analyzed using the Nanostring nCounter® platform and validated by quantitative real-time polymerase chain reaction. Differentially expressed genes were analyzed by the Ingenuity Pathway Analysis and Panther Gene Ontology tools. Results Over 110 genes were differentially expressed between LN and healthy control kidney biopsies. Although there was considerable molecular heterogeneity between LN biopsies at diagnosis and flare, for about half the LN patients gene expression from the first LN biopsy clustered with the repeated LN biopsy. However, in all patients, a set of eight interferon alpha-controlled genes had a significantly higher expression in the diagnostic biopsy compared with the flare biopsy. In contrast, nine tumor necrosis factor alpha-controlled genes had higher expression in flare biopsies. Conclusions There is significant heterogeneity in immune-gene expression of kidney tissue from LN patients. There are limited but important differences in gene expression between LN flares, which may influence treatment decisions.

Patient Outcomes in Renal-Limited Antineutrophil Cytoplasmic Antibody Vasculitis With Inactive Histology

Introduction Little is known about the anticipated disease course for individuals who present with renal-limited antineutrophil cytoplasmic antibody (ANCA)−associated vasculitis but who lack inflammation on a kidney biopsy. The impact of immunosuppression on renal and overall survival is unknown. Methods Patients were recruited from 2005 to 2016 from 8 centers worldwide (N = 16) for this descriptive study. All had positive ANCA, elevated serum creatinine with active urine sediment, histologic evidence of pauci-immune glomerulonephritis without active lesions, and had no evidence of extrarenal vasculitis. We describe the characteristics of this cohort and the differences in the clinical, histologic, and therapeutic parameters of those who developed primary outcomes of end-stage renal disease (ESRD) and vasculitis relapse. Results The cohort was 63% Caucasian, and 75% were men, with a median age of 62 years. At entry, the mean ± SD estimated glomerular filtration rate (eGFR) was 24 ± 20 ml/min per 1.73 m2, and 5 patients required dialysis. Twelve patients received immunosuppressive therapy, 25% experienced disease relapse, and 38% developed ESRD. Patients who developed ESRD had lower baseline eGFRs (8 ± 5 ml/min per 1.73 m2 vs. 35 ± 18 ml/min per 1.73 m2; P = 0.001) and more often required dialysis at presentation (83% vs. 0%; P = 0.001). Patients who relapsed were less likely to receive immunosuppression (25% for the relapsed group vs. 92% for the nonrelapsed group; relative risk: 0.27, risk difference: 67%; P = 0.03). Conclusion Among these patients, lower initial eGFR and dialysis dependence at presentation might increase the risk for ESRD. Immunosuppression did not affect renal outcomes in this sample of patients but was associated with a reduced risk for vasculitis relapse. More information is needed on factors that predict treatment response in this high-risk group.

Limited reliability of the spot urine protein/creatinine ration in the longitudinal evaluation of patients with lupus nephritis

Introduction Cross-sectional studies document that the spot protein/creatinine ratio (PCR) is often an inaccurate estimate of proteinuria magnitude compared with the 24-hour PCR, which is the gold standard. However, the extent to which the inaccuracy of the spot PCR varies over time and between individuals has not previously been reported. We address these crucial questions using a unique database, an National Institutes of Health trial in which lupus nephritis (LN) patients (N = 103) provided spot PCR testing each month and 24-hour PCR testing every 3 months for up to 15 months after induction therapy. Methods A gold standard proteinuria trend line was constructed for each patient by joining the points that represented the serial 24-hour PCR values of the patient. The spot PCR values of the patient were then plotted in relationship to the 24-hour PCR trend line. Using our previous work, which estimated the 95% confidence intervals for the 24-hour PCR at specific levels, we determined in each patient whether the spot PCR values were “reliable,” “problematic,” or “unreliable.” The sequential spot PCR of the patients deviated widely and often from the 24-hour PCR trend line, to the extent that, if the spot PCR results were used in real time for clinical decision-making, it was likely management errors would occur. Results Spot PCRs were reliable in 41%, problematic in 24%, and unreliable in 35% of patients. Those with unreliable spot PCRs could not be predicted and were more likely to respond poorly to treatment. Conclusion The spot PCR should not be used for management of LN, and perhaps, other glomerulopathies.

Management Lessons from Clinical Trials of Kidney Disease in Systemic Lupus Erythematosus

Clinically significant lupus nephritis occurs in about 40% of the overall systemic lupus erythematosus population. Despite aggressive therapy with anti-inflammatory and immunosuppressive drugs, chronic kidney damage and kidney failure are common in lupus nephritis patients. Also, standard-of-care treatment regimens are associated with significant toxicity and patient morbidity. To address this problem, a number of prospective, controlled, randomized clinical trials of potential new therapies have been undertaken recently in lupus nephritis. Unfortunately, none of these trials succeeded in demonstrating better renal outcomes or less toxicity than the standard-of-care approaches. Despite these failures, all of the trials provide important insights into the clinical behavior of lupus nephritis, which can be translated into more effective management strategies. This chapter examines lessons from lupus nephritis clinical trials and uses these lessons to build a new framework for future trials of new therapeutics.

The Clinical Evaluation of Kidney Disease in Systemic Lupus Erythematosus

Abstract Kidney injury is common in patients with systemic lupus erythematosus (SLE), most often due to immune complexes that accumulate in glomeruli, resulting in lupus nephritis. Glomerular immune complexes provoke an inflammatory response that damages the renal parenchyma. Lupus nephritis is an important cause of morbidity and mortality in SLE, suggesting that patients with lupus nephritis have a more severe form of systemic lupus. Lupus nephritis often responds to treatment. The best outcomes occur when nephritis is diagnosed and treated early. This chapter discusses the evaluation of SLE patients for lupus nephritis.

Lupus nephritis: MAINTAINing perspective in lupus nephritis trials

Despite aggressive therapy, lupus nephritis (LN) remains an important predictor of morbidity in patients with systemic lupus erythematosus. Clinical trials of novel drugs have not improved LN outcomes; however, re-analysis of well-characterized cohorts has identified surrogate end points of long-term renal survival, which will facilitate testing and qualification of novel treatments.