Faculty Bibliography

Background: Dent disease is a rare X-linked disorder characterized by increased low molecular weight proteins (LMWP) and hypercalciuria. Patients often develop nephrocalcinosis, kidney stones, or chronic kidney disease (CKD), but the phenotype of Dent disease is variable which can make diagnosis difficult. Better understanding of the pathological features that suggest Dent disease could be crucial for making an early and correct diagnosis. Methods: Clinical renal pathology reports and slides (where available) were collected from 30 male patients in eight countries who had previously undergone clinically indicated renal biopsy. Renal histopathological features were characterized and their association with kidney function was assessed. Results: Median (25th, 75th) age at biopsy was 7.5 (5, 19) years with an estimated glomerular filtration rate (eGFR) of 69 (44, 94) ml/min/1.73 m² and a 24 h urine protein of 2000 (1325, 2936) mg. All patients had increased excretion of LMWP when it was assessed (24/24), and 80 % (20/25) had hypercalciuria. 28 % (8/28) had a history of kidney stones and 14 % (3/21) had rickets. 13 % (4/30) of patients had a repeat biopsy for steroid-resistant proteinuria. Prominent histological findings included focal global glomerulosclerosis in 83 % of patients (25/30) affecting mean +/- SD glomeruli as of 16 % +/- 19 %, mild segmental foot process effacement in 57 % (13/23), focal interstitial fibrosis in 60 % (18/30), interstitial lymphocytic infiltration in 53 % (16/30) and tubular injury in 70 % (21/30). Nephrocalcinosis was reported in 20 % (6/ 30). Focal segmental glomerulosclerosis (FSGS) was documented in only 7 % (2/30). Lower eGFR at biopsy was associated with a higher percentage of globally sclerotic glomeruli (Figure 1), as well as foot process effacement, and interstitial inflammation (all P<0.05). Conclusion: Global glomerulosclerosis is commonly seen in Dent disease, well beyond that expected for age, and is associated with reduced kidney function. The association of foot process effacement and kidney function suggests a role for podocyte pathology in disease progression. Given the marked increase in globally sclerotic glomeruli with age, Dent disease must be recognized early in all males that present with unexplained proteinuria and stones so that treatments can be initiated as soon as possible. (Figure Presented)

BACKGROUND:Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. METHODS AND DESIGN/METHODS:Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with i.v. rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. DISCUSSION/CONCLUSIONS:This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.

Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.

Introduction & Objectives: Genetic disorders are among the causes of the most severe stone disease. Among them, primary hyperoxaluria (PH), cystinuria, APRT deficiency, and Dent disease can also be associated with loss of kidney function. Due to their rarity, however, understanding of the impact of these stone diseases on kidney function over time is limited. We performed a cross-sectional study of kidney function in patients with each of these disorders over a range of ages. Material & Methods: Voluntary observational registries of the Rare Kidney Stone Consortium were queried. 155 patients with PH, 53 with cystinuria, 34 with APRT deficiency, and 78 with Dent disease had serum creatinine values available prior to development of end stage kidney failure. Serum creatinine at first presentation was used for calculation of eGFR. Kidney function was calculated by MDRD equation in adults and Schwartz equation in children. Spline curve was used to check linearity of plots. Results were compared with normal eGFR of 116 at 20 years of age with decline of 7.5 ml/min/1.73m2BSA per decade after age 30 years (Lindeman J Am Ger Soc, 1985). Results: Age at eGFR was 16.1+/-17.4, 39.8+/-16.7, 25.9+/-19.1, and 12.4+/-10.0 years (mean+/- SD) and the number of stones at presentation was 4.2+/-10.0, 1.9+/-1.8, 1.7+/-4.8, and 3.1+/-3.9 (mean+/-SD) in PH, cystinuria, APRT deficiency, and Dent patients, respectively. eGFR was 91.5, 80.2, 69.8, and 91.5 ml/min/1.73m2BSA in PH, cystinuria, APRT deficiency, and Dent disease patients, respectively. The change in eGFR per decade was -15 (2.1) ml/min/1.73m2 BSA (SE) in PH, -12 (2.2) in cystinuria, -16 (3.9) in APRT deficiency, and -26 (7.9) in Dent disease. Conclusions: Cross sectional data in patients with PH, cystinuria, APRT deficiency and Dent disease shows more rapid decline in kidney function by decade than observed in healthy subjects. Whether kidney damage is related to stone burden or to other factors remains to be determined. The distinction will be of importanc!

Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A(2) receptor (anti-PLA(2)R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA(2)R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA-associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis.

Genetics plays an important role in establishing susceptibility to nephrolithiasis, although diet and other environmental factors make major contributions. In a small number of patients, the genetic causes of stones are more clearly established. Four of these hereditary diseases include primary hyperoxaluria, Dent disease, cystinuria, and adenine phosphoribosyltransferase deficiency, which results in 2,8-dihydroxyadenine stones. Patients with these disorders often experience recurring stones from early childhood, requiring frequent hospitalizations and procedures. They are at risk of kidney damage and chronic kidney disease. Because of their rarity, these four disorders are difficult to study and recognize. This in turn slows progress toward effective therapies and increases the risk of misdiagnosis or diagnosis late in the course of the disease. Therefore, patients may experience unnecessary and harmful treatments and accelerated loss of kidney function. In this article, we will review the pathogenesis, clinical presentation, diagnosis of and treatments for these four disorders. 2011 Springer Science+Business Media, LLC

Gout recently passed rheumatoid arthritis to become the most common inflammatory arthritis in the United States (US). However, epidemiologic studies indicate that the quality of gout management is suboptimal owing to both patient and physician issues. Only three options for urate-lowering therapy are currently available in the US: allopurinol, probenecid, and recently, febuxostat. Probenecid is generally safe except for the occurrence of urolithiasis, but is only effective for the subset of patients with better kidney function. Allopurinol use is limited due to its side effects, potential toxicity of uncertain magnitude in patients with renal disease, and failure to achieve targeted serum urate levels. In part this failure may be due to the necessity for it to be titrated for optimal therapeutic effect. Febuxostat is a new medication that may offer several advantages and can be given as an alternative to allopurinol. We review the basic biology and clinical performance of febuxostat, and consider the potential utility of this agent in comparison to the older, better-established gout therapeutics

Background. The increasing prevalence of adynamic bone disease (ABD) is a rising concern for end-stage renal disease (ESRD) patients. There is also a concern about the potential role of renal bone disease in contributing to cardiovascular disease in these patients. Metabolic studies have implicated that ABD may be associated with increased soft tissue and cardiac calcifications. Methods. Ten hemodialysis (HD) patients with parathyroid hormone (PTH) levels &lt; 450 pg/ml underwent iliac crest bone biopsy (Bx), electron beam computed tomography of the heart, dual energy x-ray absorptiometry (DXA), and monitoring of their calcium, phosphorus, and PTH levels. Results. Six patients had ABD, 4 patients had mixed uremic bone disease (Mx). The ABD patients had a wide range of coronary artery calcification (CAC) scores, from mild to very severe plaque burden. Nine patients were osteopenic or osteoporotic by DXA. There were no correlations between the results of Bx, CAC score, DXA, or calcium, phosphorus, or PTH levels. When we separated the patients by diagnosis (ABD vs. Mx) there was still no statistical significance between groups for CAC scores, age, time on dialysis, oral calcium load, or metabolic parameters. Subjects were also divided into groups by CAC score: those with scores &lt; 400 and those with scores &gt; 400. There were no significant differences between these groups when comparing age, time on dialysis, calcium load, metabolic parameters, or bone disease. Conclusion. We found that patients with low-normal PTH levels do not have uniform bone pathology or predictable CAC scores. Although this study is limited by its small patient population, it does not support the suggestion of others that ABD contributes to higher tissue calcifications.