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.

Revision of the Failed Thumb Carpometacarpal Arthroplasty.

PURPOSE: To evaluate the outcome of revision surgery for failed thumb carpometacarpal (CMC) arthroplasty. METHODS: We retrospectively analyzed 32 patients with failed thumb CMC arthroplasty. The primary reason for revision was pain caused by metacarpal subsidence. Revision surgery included soft tissue interposition and distraction pinning to address the metacarpal subsidence. Additional ligament reconstruction was performed in patients with thumb instability. Eight patients required additional metacarpophalangeal joint fusion for concomitant joint hyperextension. Eleven required additional partial excision of the trapezoid for concomitant scaphotrapezoidal joint arthritis. All patients were evaluated clinically and radiographically. RESULTS: Mean follow-up was 57 months (range, 24-121 months). Pain levels evaluated by visual analog scale were significantly reduced in all patients after revision surgery. Mean grip strength and key pinch strength significantly increased. Twenty-seven patients achieved good functional results; those for 5 patients were fair. CONCLUSIONS: This study showed that revision surgery with distraction pinning and soft tissue interposition with or without ligament reconstruction was an effective treatment for failed CMC arthroplasty of the thumb. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Discontinuation of tenofovir disoproxil fumarate for presumed renal adverse events in treatment-naïve HIV-1 patients: meta-analysis of randomized clinical studies.

BACKGROUND: Safety and efficacy of tenofovir disoproxil fumarate (TDF) as a component of antiretroviral therapy (ART) have been demonstrated in clinical trials. TDF nephrotoxicity has been reported in both HIV-infected and noninfected patients. This meta-analysis explored the frequency of discontinuation attributed to renal adverse events (AEs) in randomized, controlled clinical studies that used TDF-containing regimens for ART-naïve, HIV-infected patients. METHODS: A literature search of 4 electronic databases through October 31, 2013 was utilized. RCTs included were limited to randomized, prospective, comparative design in ART treatment-naïve adults with HIV-1 infections receiving ART. Studies included trials containing TDF treatment regimens, with or without a non-TDF control group. Study design, follow-up, size of study population, treatment group, patient demographics, number of patients exposed to TDF or non-TDF control, baseline characteristics, investigator-defined criteria for renal AEs, and number of discontinuations due to a presumed renal AEs were extracted. RESULTS: Twenty-one clinical studies met the selection criteria. Treatment duration ranged from 48 to 288 weeks. Renal AEs led to study drug discontinuation in 44 of 10,129 patients exposed to TDF (0.43%; 95% CI, 0.32%-0.58%) and 2 of 2,013 patients exposed to non-TDF-containing regimens (0.10%; 95% CI, 0.01%-0.36%). In 5 randomized, controlled studies that included a non-TDF comparator, the estimated risk difference between the treatment groups (TDF vs non-TDF) was 0.50% (95% CI, 0.13%-0.86%; P = .007). CONCLUSIONS: In clinical studies using TDF-containing regimens, the rate of discontinuations due to renal AEs was low, but was slightly higher than in studies using non-TDF comparators.

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.

COVID-19-Associated Acute Kidney Injury and Quantified Protein Catabolic Rate: A Likely Effect of Cytokine Storm on Muscle Protein Breakdown.

RATIONALE & OBJECTIVES: Previously we reported a cohort of patients with coronavirus disease 2019 (COVID-19)-associated acute kidney injury (AKI) with striking biochemical evidence of tissue breakdown in the absence of apparent rhabdomyolysis. We sought to quantify the extent of tissue catabolism in similar patients. STUDY DESIGN: During acute peritoneal dialysis (PD) in patients with COVID-19-associated AKI, we measured urea Kt/V adequacy and calculated the daily urea nitrogen generation rate while quantifying daily protein intake. SETTING & POPULATION: We did calculations in 8 patients with COVID-9-associated AKI undergoing acute PD at Mount Sinai Hospital in New York City. As a comparator, we obtained urea kinetic parameters from our database of ambulatory patients receiving maintenance PD. EXPOSURE OR PREDICTORS: 8 patients with COVID-19-associated AKI undergoing acute PD. OUTCOMES: Urea nitrogen generation rate in relation to daily protein intake. ANALYTICAL APPROACH: Urea nitrogen generation rate from urea kinetics was related to measured daily dietary protein intake in these patients and we compared it with this relationship in ambulatory maintenance PD patients for whom both parameters were calculated from urea kinetics. RESULTS: Urea nitrogen generation rate in patients with AKI was 10.2 ± 5 g/d, which is more than 2-fold higher than for stable outpatients receiving maintenance PD (4.7 ± 3 g/d) despite similar dietary protein intake (74.8 ± 11 vs 67.2 ± 29 g/d, respectively). This strongly suggests endogenous protein breakdown, probably from muscle. Urea nitrogen generation rate in these patients with AKI corresponds to 315 g/d of ongoing muscle breakdown and cumulative 2.5 kg of muscle breakdown during the early course of AKI. LIMITATIONS: Small number of participants and assumptions in comparing urea nitrogen generation rate with protein intake. CONCLUSIONS: In highly catabolic patients, an endogenous source of urea generation such as muscle protein breakdown seems to be the most likely explainable cause for our findings. This is the first study that we are aware of to quantify the degree of endogenous protein breakdown induced by COVID-19-related cytokine storm.

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.

Acute Kidney Injury in Hospitalized Patients with COVID-19.

IMPORTANCE: Preliminary reports indicate that acute kidney injury (AKI) is common in coronavirus disease (COVID)-19 patients and is associated with worse outcomes. AKI in hospitalized COVID-19 patients in the United States is not well-described. OBJECTIVE: To provide information about frequency, outcomes and recovery associated with AKI and dialysis in hospitalized COVID-19 patients. DESIGN: Observational, retrospective study. SETTING: Admitted to hospital between February 27 and April 15, 2020. PARTICIPANTS: Patients aged ≥18 years with laboratory confirmed COVID-19 Exposures: AKI (peak serum creatinine increase of 0.3 mg/dL or 50% above baseline). Main Outcomes and Measures: Frequency of AKI and dialysis requirement, AKI recovery, and adjusted odds ratios (aOR) with mortality. We also trained and tested a machine learning model for predicting dialysis requirement with independent validation. RESULTS: A total of 3,235 hospitalized patients were diagnosed with COVID-19. AKI occurred in 1406 (46%) patients overall and 280 (20%) with AKI required renal replacement therapy. The incidence of AKI (admission plus new cases) in patients admitted to the intensive care unit was 68% (553 of 815). In the entire cohort, the proportion with stages 1, 2, and 3 AKI were 35%, 20%, 45%, respectively. In those needing intensive care, the respective proportions were 20%, 17%, 63%, and 34% received acute renal replacement therapy. Independent predictors of severe AKI were chronic kidney disease, systolic blood pressure, and potassium at baseline. In-hospital mortality in patients with AKI was 41% overall and 52% in intensive care. The aOR for mortality associated with AKI was 9.6 (95% CI 7.4-12.3) overall and 20.9 (95% CI 11.7-37.3) in patients receiving intensive care. 56% of patients with AKI who were discharged alive recovered kidney function back to baseline. The area under the curve (AUC) for the machine learned predictive model using baseline features for dialysis requirement was 0.79 in a validation test. CONCLUSIONS AND RELEVANCE: AKI is common in patients hospitalized with COVID-19, associated with worse mortality, and the majority of patients that survive do not recover kidney function. A machine-learned model using admission features had good performance for dialysis prediction and could be used for resource allocation.

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.

Kidney disease in patients with HIV infection and AIDS.

As patients infected with human immunodeficiency virus (HIV) live longer while receiving antiretroviral therapy, kidney diseases have emerged as significant causes of morbidity and mortality. Black race, older age, hypertension, diabetes, low CD4(+) cell count, and high viral load remain important risk factors for kidney disease in this population. Chronic kidney disease should be diagnosed in its early stages through routine screening and careful attention to changes in glomerular filtration rate or creatinine clearance. Hypertension and diabetes must be aggressively treated. Antiretroviral regimens themselves have been implicated in acute or chronic kidney disease. The risk of kidney disease associated with the widely used agent tenofovir continues to be studied, although its incidence in reported clinical trials and observational studies remains quite low. Future studies about the relationship between black race and kidney disease, as well as strategies for early detection and intervention of kidney disease, hold promise for meaningful reductions in morbidity and mortality associated with kidney disease.

Serum cystatin C and increased coronary heart disease prevalence in US adults without chronic kidney disease.

Previous studies indicated that serum cystatin C, a marker of renal function, was associated with cardiovascular disease (CVD). However, few data about this association are available for persons without chronic kidney disease or albuminuria. Data from 4,991 subjects in the Third National Health and Nutrition Examination Survey with an estimated glomerular filtration rate > or =60 ml/min/1.73 m2 without micro- or macroalbuminuria were analyzed. Subjects were categorized into quartiles of serum cystatin C and compared for prevalence of CVD. CVD was defined as a history of myocardial infarction, angina, or stroke. After age standardization, prevalences of CVD from the lowest to highest quartile of serum cystatin C were 6.0%, 8.8%, 11.8%, and 16.7% (p-trend = 0.006). Also, age-standardized prevalences of myocardial infarction across quartiles of serum cystatin C were 1.9%, 4.4%, 6.6%, and 8.6%; age-standardized prevalences of angina were 2.4%, 4.4%, 4.2%, and 7.1%; and age-standardized prevalences of stroke were 2.5%, 1.6%, 3.5%, and 4.4% (each p-trend <0.05). Each 1-SD higher serum cystatin C level was associated with a multivariate prevalence ratio of CVD of 1.55 (95% confidence interval [CI] 1.13 to 2.13), and multivariate-adjusted prevalence ratios were 1.44 (95% CI 1.01 to 2.07), 1.64 (95% CI 1.02 to 2.64), and 1.65 (95% CI 1.06 to 2.56) for myocardial infarction, angina, and stroke, respectively. In conclusion, a graded association exists between higher serum cystatin C and increased CVD prevalence in patients without established chronic kidney disease.

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.

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.

Elevated homocysteine levels in patients with end-stage renal disease.

PURPOSE: To examine the effect of hemodialysis on plasma homocysteine levels, and the relationship of these values to clinical cardiovascular events in patients with end-stage renal disease (ESRD). METHODS: Adults undergoing chronic hemodialysis were studied at baseline and at six months. Their clinical histories were obtained at the baseline visit, and measurements of plasma homocysteine concentration were made immediately prior to and following routine dialysis. The occurrence of clinical cardiovascular events was assessed over six months. RESULTS: We enrolled 147 patients (85 men and 62 women, age 58 +/- 15 years) who required hemodialysis for 3.4 +/- 3.4 years (mean +/- SD). The median homocysteine level for this population (including both pre- and post-dialysis values) was 17.3 micromoles/L. Mean pre-dialysis plasma homocysteine levels of patients with clinical cardiovascular disease did not differ significantly from those without the disease (22.5 +/- 9.9 vs. 25.4 +/- 24.5 micromoles/L, respectively), nor did post-dialysis levels differ between these populations. During six months follow-up, rates of ischemic events were not related to hyperhomocysteinemia. The difference between mean pre- and post-dialysis homocysteine levels (26.3 +/- 19.7 and 15.6 +/- 11.4 micromoles/L, respectively) and the decline in homocysteine over the course of a single dialysis treatment session (10.3 +/- 10.2 micromoles/L) were highly significant (p<0.0005). CONCLUSIONS: Plasma homocysteine levels were elevated in 82% of 147 patients with ESRD and fell to the normal range in a majority of patients during a single dialysis treatment session. Mean pre-dialysis levels did not change significantly over six months, however, and plasma homocysteine levels did not predict cardiovascular events in this population. There was also a trend towards worse outcomes in patients with lower homocysteine levels, which correlates to findings from recent studies. Further studies are needed to clarify the association between hyperhomocysteinemia and coronary risk in patients with ESRD.