Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis.

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

Cardiovascular pathophysiology in chronic kidney disease: opportunities to transition from disease to health.

BACKGROUND: Chronic kidney disease (CKD) is common, and is associated with a high burden of cardiovascular disease. This cardiovascular risk is incompletely explained by traditional risk factors, calling attention to a need to better understand the pathways in CKD contributing to adverse cardiovascular outcomes. FINDINGS: Pathophysiological derangements associated with CKD, including disordered sodium, potassium, and water homeostasis, renin-angiotensin-aldosterone and sympathetic activity, anemia, bone and mineral metabolism, uremia, and toxin accumulation may contribute directly to progression of cardiovascular disease and adverse outcomes. CONCLUSION: Improving cardiovascular health in patients with CKD requires improved understanding of renocardiac pathophysiology. Ultimately, the most successful strategy may be prevention of incident CKD itself.

APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy.

A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 × 10(-2) to 5 × 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 × 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.

Paraneoplastic glomerulopathy secondary to retroperitoneal sarcoma: a case report.

Glomerulopathy is a rare form of paraneoplastic disease. We present the second reported case of paraneoplastic glomerulopathy due to a retroperitoneal sarcoma. The patient presented with generalized edema and nephrotic syndrome. CT scan showed two large retroperitoneal masses. One large retroperitoneal mass was resected. Post-operatively, she developed kidney failure and biopsy showed minimal change disease. With steroid therapy, patient's symptoms went into remission. We hypothesize that minimal change paraneoplastic glomerulopathy developed due to damage from cytokines released from a T-cell mediated response to the malignancy.

HIV and CKD epidemiology.

Nephrologists can serve many important functions for HIV-infected patients, including identifying risks for developing kidney disease, detecting and diagnosing kidney disease, distinguishing antiretroviral-induced kidney injury from kidney disease in the setting of antiretroviral therapy, comanaging the clinical course and complications of CKD, and preparing patients for dialysis and/or transplantation. The epidemiology of kidney disease in HIV informs us for these functions by describing the natural history of disease, its frequent occurrence in high-risk communities, and its potential causes. Risk factors that drive CKD in HIV are black race, hypertension, diabetes, HIV viral replication with low CD4 cell counts, high viral load or acquired immune deficiency syndrome-defining conditions, and antiretroviral agents with nephrotoxic potential. The prevalence of these risk factors in any population determines the magnitude of the problem, which can range from as low as 2% to as high as 30%. Recent research focuses on kidney health in HIV. Important links between HIV viral replication and glomerular filtration rate, even in patients with normal kidney function, are now being reported. A review of these data provides the foundation for a better understanding of kidney disease and, hopefully, better treatment for patients with HIV.

Diminished benefits of drug-eluting stents versus bare metal stents in patients with severe renal insufficiency.

BACKGROUND: Since their introduction, the use of drug-eluting stents (DES) has increasingly become standard practice due to their decreased rates of in-stent restenosis and target lesion revascularization (TLR) rates in comparison to bare metal stents (BMS). However, these benefits have not been reproduced in patients with severe renal disease (SRD). This study compared TLR rates in patients with severe renal insufficiency treated with DES vs. BMS. METHODS: Between 2003 and 2006, we collected data on 6,220 consecutive patients receiving either DES or BMS. Both groups were similar in angiographic and clinical variables. TLR rates at 270 days and 1 year were then compared between patients receiving DES or BMS with varying creatinine clearance (CrCl). RESULTS: At 1 year after PCI, TLR rates were significantly lower for DES in patients with CrCl >60 (5 vs. 9.3%; p < 0.0001). However, in patients with CrCl <40 ml/min or on dialysis there was no significant difference in TLR rates for DES vs. BMS. CONCLUSION: While DES showed improved clinical outcomes in patients with normal and mildly impaired renal function, they showed no benefit over BMS in patients with moderate to severe renal insufficiency. Coupled with the possibly increased risk of late stent thrombosis with DES, BMS may be a more appropriate and safer stent in this population.

Estimating glomerular filtration rate in patients with HIV infection.

Accurate markers of glomerular filtration rate in human immunodeficiency virus (HIV)-infected persons would be useful for early diagnosis of HIV-associated nephropathy and other glomerular diseases, and for identifying patients at high risk for subsequent declines in kidney function who also may develop cardiovascular disease or renal complications from antiretroviral agents or other therapies. Creatinine-based estimates of glomerular filtration rate have not been tested rigorously in HIV-infected persons. Their accuracy has been questioned in malnourished patients, with or without a wasting syndrome, and in those treated with anabolic steroids. Cystatin C level is increased in HIV, but more studies are needed to determine its association with kidney function, inflammation, and long-term outcomes.

The 3-year renal safety of a tenofovir disoproxil fumarate vs. a thymidine analogue-containing regimen in antiretroviral-naive patients.

BACKGROUND: Cases of renal dysfunction in patients receiving tenofovir disoproxil fumarate (TDF) have been reported. We analyzed the renal safety of TDF compared with thymidine analogue-containing (control) regimens through 144 weeks from two clinical trials in antiretroviral-naive HIV-infected patients. METHODS: We evaluated the changes in renal parameters in 1111 patients (TDF, n = 556; control, n = 555) who were enrolled in two randomized, controlled trials (Studies 903 and 934) comparing TDF vs. either stavudine or zidovudine in combination with efavirenz and either lamivudine or emtricitabine. The studies included patients with serum creatinine less than 1.5 mg/dl, serum phosphorus at least 2.2 mg/dl and estimated glomerular filtration rate by Cockcroft-Gault at least 60 and at least 50 ml/min at screening. RESULTS: Baseline characteristics were similar between groups. No patient discontinued due to renal abnormalities in the TDF arm. Through 144 weeks, the proportion of patients who experienced confirmed abnormalities in serum creatinine (>1.5 mg/dl) or serum phosphorus (<2.0 mg/dl) was less than 1% in both groups; a similar proportion of patients experienced urine proteinuria at least 100 mg/dl (TDF, 5%; control, 6%). The median change from baseline to week 144 in glomerular filtration rate was -2 and 3 ml/min by Cockcroft-Gault, and -2 and -1 ml/min per 1.73 m by modification of diet in renal disease in the TDF and control groups (P < 0.05), respectively. CONCLUSION: In two randomized, controlled trials, small differences in glomerular filtration rate over time were noted but no clinically relevant renal disease or adverse events were demonstrated in antiretroviral-naive patients treated with TDF through 144 weeks. Additional studies on renal health and renal safety in HIV are important goals for future clinical trials.

Chronic kidney disease in HIV infection: an urban epidemic.

Kidney disease is an important complication of HIV, particularly in minority populations. We describe the burden of chronic kidney disease among 1239 adults followed at an urban AIDS center, with an estimated prevalence of 15.5% (n = 192). Independent predictors of kidney disease included older age, black race, hepatitis C virus exposure, and lower CD4 cell count. These data suggest that chronic kidney disease remains a common complication of HIV infection in the era of antiretroviral therapy.

Grand rounds: nephrotoxicity in a young child exposed to uranium from contaminated well water.

CONTEXT: Private wells that tap groundwater are largely exempt from federal drinking-water regulations, and in most states well water is not subject to much of the mandatory testing required of public water systems. Families that rely on private wells are thus at risk of exposure to a variety of unmeasured contaminants. CASE PRESENTATION: A family of seven--two adults and five children--residing in rural northwestern Connecticut discovered elevated concentrations of uranium in their drinking water, with levels measured at 866 and 1,160 microg/L, values well above the U.S. Environmental Protection Agency maximum contaminant level for uranium in public water supplies of 30 microg/L. The uranium was of natural origin, and the source of exposure was found to be a 500-foot well that tapped groundwater from the Brookfield Gneiss, a geologic formation known to contain uranium. Other nearby wells also had elevated uranium, arsenic, and radon levels, though concentrations varied widely. At least one 24-hr urine uranium level was elevated (> 1 microg/24 hr) in six of seven family members (range, 1.1-2.5 microg/24 hr). To assess possible renal injury, we measured urinary beta-2-microglobulin. Levels were elevated (> 120 microg/L) in five of seven family members, but after correction for creatine excretion, the beta-2-microglobulin excretion rate remained elevated (> 40 microg/mmol creatinine) only in the youngest child, a 3-year-old with a corrected level of 90 microg/mmol creatinine. Three months after cessation of well water consumption, this child's corrected beta-2-microglobulin level had fallen to 52 microg/mmol creatinine. SIGNIFICANCE: This case underscores the hazards of consuming groundwater from private wells. It documents the potential for significant residential exposure to naturally occurring uranium in well water. It highlights the special sensitivity of young children to residential environmental exposures, a reflection of the large amount of time they spend in their homes, the developmental immaturity of their kidneys and other organ systems, and the large volume of water they consume relative to body mass.

Assessing kidney function in HIV infection.

Chronic kidney disease often goes unrecognized, and the NIH encourages clinical laboratories to report glomerular filtration rate (GFR) estimates when they report serum creatinine levels. Chronic kidney disease based on estimated GFRs below 60 mL/min/1.73m2 is seen in as many as 10% of persons with HIV infection and even more frequently when urinary protein excretion is measured. The Cockcroft-Gault formula and Modification of Diet in Renal Disease (MDRD) equation are the most widely used to estimate GFR. Although which estimate is more reliable is still debated, both are superior to serum creatinine levels alone for evaluating kidney function. The Cockcroft-Gault formula is the standard FDA measure for recommended renal dose adjustment; the MDRD equation is considered the most reliable predictor of GFR within the range of 20 to 60 mL/min/1.73m2. Neither equation has been validated in HIV or other special populations. Patients with proteinuria or a reduced GFR should undergo further evaluation and referral to a nephrologist.

Therapy insight: how changes in renal function with increasing age affect cardiovascular drug prescribing.

Age is well recognized as a powerful prognostic factor in the setting of cardiovascular disease. With the aging of the US population, it is projected that more than 50 million people will be aged over 65 years by the year 2020. This growing elderly population has increased rates of morbidity and mortality owing to cardiovascular disease; however, proven therapies for prevention and treatment are often underused in older patients, largely because physicians perceive them as being frail and have limited understanding of age-related unique adverse and therapeutic effects. Advancing age is associated with a number of physiologic and pathophysiologic changes that impact the toxic effects, efficacy and dosing of many medications. Decreases in lean muscle mass affect the volume of distribution, and reductions in hepatic function affect the metabolism of many medications. Age-related reductions in renal function might have the most profound impact on the safety profile and dosing of medications in elderly patients. The strong association between renal and cardiovascular disease makes recognition of renal dysfunction and appropriate dose adjustment particularly important in elderly patients with cardiovascular disease. This article reviews current approaches to the estimation of renal function, and unique considerations related to prescribing medication for elderly patients with concomitant renal and cardiovascular disease.

Medical risks in living kidney donors: absence of proof is not proof of absence.

Living-kidney donation has become increasingly widespread, yet there has been little critical analysis of existing studies of long-term medical outcomes in living donors. This review analyzes issues in study design that affect the quality of the evidence and summarizes possible risk factors in living donors. Virtually all studies of long-term outcomes in donors are retrospective, many with large losses to follow-up, and therefore are subject to selection bias. Most studies have small sample sizes and are underpowered to detect clinically meaningful differences between donors and comparison groups. Many studies compare donors with the general population, but donors are screened to be healthier than the general population and this may not be a valid comparison group. Difficulties in measurement of BP and renal function may underestimate the impact of donation on these outcomes. Several studies have identified possible risk factors for development of hypertension, proteinuria, and ESRD, but potential vulnerability factors in donors have not been well explored and there is a paucity of data on cardiovascular risk factors in donors. Prospective registration of living kidney donors and prospective studies of diverse populations of donors are essential to protect living donors and preserve living-kidney donation.

Highly active antiretroviral therapy and the epidemic of HIV+ end-stage renal disease.

The rise in the number of patients with HIV-associated nephropathy and HIV-infection with end-stage renal disease (HIV+ ESRD) continues to be a substantial concern for the ESRD program. In order to assess the impact of highly active antiretroviral therapy (HAART) on the progression of patients with AIDS to the development of ESRD and to project the prevalence of HIV+ ESRD through 2020, a mathematical model of the dynamics of HIV+ infection in the ESRD population was developed. Epidemiologic data on AIDS and HIV+ ESRD among black individuals in the United States were obtained since 1991 from the Centers for Disease Control and Prevention and US Renal Data System, respectively. The model was constructed to predict the prevalence of HIV+ ESRD incorporating the current rate of growth in AIDS prevalence. Two possible trends were considered: linear AIDS growth and exponential AIDS growth. The likely effectiveness of HAART in slowing progression to HIV+ ESRD was estimated from the best fit of the model to the data after 1995, when HAART was introduced. The model was then used to evaluate recent data and to project the prevalence of HIV+ ESRD through 2020. The model suggested that HAART has reduced the rate of progression from AIDS to HIV+ ESRD by 38%. The model projected an increase in HIV+ ESRD prevalence in the future as a result of the increase in the AIDS population among black individuals. This increase was predicted even assuming a 95% reduction in the progression from AIDS to HIV+ ESRD. Despite the potential benefit of HAART, the prevalence of HIV+ ESRD in the United States is expected to rise in the future as a result of the expansion of the AIDS population among black individuals. It is concluded that prevention of progression to ESRD should focus on early antiretroviral treatment of HIV-infected patients who have evidence of HIV-associated nephropathy.

The clinical epidemiology and course of the spectrum of renal diseases associated with HIV infection.

BACKGROUND: While an understanding of the epidemiology and clinical course of HIV-associated nephropathy (HIVAN) is growing, little is known about the risk factors and clinical course of the other renal diseases that may also occur as a complication of HIV infection. This study was undertaken to compare HIVAN to the spectrum of other kidney diseases seen among HIV-infected patients. METHODS: This retrospective cohort study included all HIV-infected patients who underwent renal biopsy during the course of their clinical care at six major medical centers. Demographic and clinical information were abstracted from each patient's clinical record. Time to initiation of renal replacement therapy was compared for patients with lesions other than HIVAN to patients with HIVAN using Cox proportional hazards regression. RESULTS: Eighty-nine patients (47 with lesions other than HIVAN and 42 with HIVAN) were available for inclusion. Patients with lesions other than HIVAN were less likely to be black (37/47 vs. 42/42, P= 0.02), more likely to have a positive hepatitis B surface antigen (10/37 vs. 4/42, P= 0.04), less likely to have the diagnosis of hypertension (24/46 vs. 31/42, P= 0.03), more likely to have a greater creatinine clearance at time of biopsy (60.6 vs. 39.0 cc/min, P= 0.008), and have a greater CD4 lymphocyte count at time of biopsy (287 vs. 187 cells/mL, P= 0.04) compared to patients with HIVAN. Lesions other than HIVAN were associated with a longer time to initiation of renal replacement therapy compared with HIVAN (HR 0.33, 95% CI 0.15-0.71, P= 0.005). Other factors associated with a longer time to renal replacement therapy included higher creatinine clearance at time of biopsy, greater CD4(+) lymphocyte count, the absence of hepatitis C antibody, and the use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The type of renal disease (HIVAN vs. other) interacted significantly with HIV-1 RNA level and the use of antiretroviral therapy (P= 0.0001 and 0.006, respectively). Among patients with lesions other than HIVAN, the presence of nondetectable HIV-1 RNA was not associated with a greater risk of progression of renal disease (HR 0.27, P= 0.24). Among patients with HIVAN, because all patients had detectable virus at the time of institution of renal replacement therapy, this highly significant association could not be quantified. Among patients with lesions other than HIVAN, the use of antiretroviral therapy was not associated with the progression to renal replacement therapy (HR 3.29, P= 0.06). Among patients with HIVAN, the use of antiretroviral therapy was associated with a slower progression to renal replacement therapy (HR 0.24, P= 0.03). CONCLUSION: Among HIV-infected patients with renal disease other than HIVAN, viral suppression and the use of antiretroviral therapy are not associated with a beneficial effect on renal function; thus, additional therapeutic strategies may need to be utilized. Because renal histology is associated with prognostic differences, these data provide outcomes information that will improve the clinical utility of renal biopsy among HIV-infected patients with renal disease.