HIV-associated kidney diseases: progress, gaps, and future directions.

Too Many for Too Few: Finding Appropriate Nephrology Referrals for Patients With CKD That Optimize Outcomes

HIV at 40: kidney disease in HIV treatment, prevention, and cure

Editorial

Moving Beyond Tools and Building Bridges: Lessons Learned From a CKD Decision Support in Primary Care

There is evidence that HIV-associated nephropathy (HIVAN) can be prevented and its progression slowed by HAART. More than 20 antiretroviral drugs and drug combinations are available, and life expectancy of HIV-infected individuals is now measured in decades. However, it is likely that more indolent forms of HIVAN remain common in the HAART era, predisposing patients to nephrotoxicity from HAART and related therapies. Indeed, the prevalence of acute renal failure and chronic kidney disease appears to be increasing among HIV-infected patients in the United States [1,2], and kidney disease has emerged as an important predictor of mortality [2,3]. Adverse effects of antiviral treatments should be considered, including their long-term renal toxicity and their role in renal scarring after acute adverse events. In addition, the burden of comorbid chronic kidney disease is likely to increase with ageing of the HIV-infected cohort, continued growth of the epidemic among susceptible minorities and increasing prevalence of HAART-related metabolic abnormalities. In this population of patients, evaluation of renal disorders and prevention of evolution toward chronic renal failure are a crucial challenge. Epidemiology of HIV-associated nephropathy and HIV-related diseases Most epidemiological data on HIVAN generated in the pre-HAART era are based on the US Renal Data System (USRDS). Initial clinical studies indicated that 10% of HIV-1-infected patients appeared to develop renal disease, of which 90% showed clinical and/or pathological features consistent with HIVAN [4,5]. Past postmortem studies also yielded a prevalence of HIVAN ranging between 1% and 15%, depending on the population [6,7]. The prevalence and distribution of HIVAN was associated strongly with African-American ancestry [8,9] as indicated by an USRDS-based report of 3653 patients with end-stage renal disease (ESRD) secondary to HIVAN during 1992 to 1997 [10]. Since the introduction of HAART, national epidemiological data show a reduction of incidence of ESRD associated with HIV-associated renal disease in the United States [11,12] contrasting with the steady increase in HIV/AIDS in the general population [13]. From a mathematical model using available epidemiological data on HIV-infected patients in the USRDS database and the Centers for Disease Control and Prevention data for HIV-seropositive patients, Blower et al.[14] suggested that HAART decreases the incidence of ESRD in patients with HIVAN and the mortality from HIV, with an overall efficacy of 23%. This trend has been attributed, in part, to beneficial effects of HAART, which was commenced in 1996. Preliminary retrospective series or case reports support the efficacy of HAART in improving outcome in HIVAN [15–19]. In a retrospective cohort study, Szczech et al.[20] reported that treatment with protease inhibitors (and prednisone) was associated with a slower decline in renal function in patients with HIVAN or other HIV-1-related renal diseases. Cosgrove et al.[18] reported another retrospective series of 23 patients with HIV-1-related nephropathies, including patients with HIVAN. Patients with HIVAN were treated with HAART and none doubled their serum creatinine. In the non-HAART group, all patients showed a doubling of serum creatinine, two patients died and eight required dialysis. One study [21], retrospectively comparing two cohorts of 102 and 33 patients with biopsy-proven-HIVAN in the pre-HAART and in the HAART eras, respectively, also argues for improvement of renal survival by HAART. However, a recent postmortem-based survey reported that 12% of African-American patients dying of HIV-1 infection have histologically confirmed HIVAN [22]. Even if HAART decreases the incidence of HIVAN in African-Americans, the prevalence of HIVAN may not change because of the improvement in the survival of these patients. The onset of HIVAN could, therefore, just be delayed. Indeed, we have recently reported a patient with biopsy-proven HIVAN despite the lack of any past or present AIDS-defining condition and HAART-controlled HIV-1 infection for at least 2 years [23] Schwartz et al.[1] developed a mathematical model of the dynamics of HIV infection in the ESRD population in order to assess the impact of HAART on the progression of patients with AIDS to the development of ESRD and to predict the prevalence of HIV-related ESRD through to 2020. The authors concluded that, despite the potential benefit of HAART, the prevalence of HIV-related ESRD in the United States would be expected to rise in the future as a result of the expansion of the number with AIDS among black individuals. Nonetheless, while prospective controlled trials evaluating HAART on HIVAN or other HIV-1-related nephropathies are not ethically acceptable, consensus guidelines recommend consideration of HAART in HIV-infected patients with chronic renal insufficiency [24]. Changes in clinicopathological presentation HIV-associated nephropathy HIVAN is an unusual form of poorly responsive glomerular disease characterized by nephrotic syndrome, focal segmental glomerulosclerosis and a rapid fulminant progression to ESRD. Proteinuria occurs in up to 30% of HIV-infected patients, but not all of these patients have HIVAN [25–27]. The true prevalence of HIVAN is not known. The geographic distribution of HIVAN is not uniform, and it depends on specific risk factors for HIV disease, including race, gender and drug use. There is a striking predilection for HIVAN among African-Americans, as is also true for focal segmental glomerulosclerosis associated with intravenous drug use [4]. HIVAN is 7–10 times more common in men than in women, and 30–60% of people with HIVAN have a history of intravenous drug use [7]. In the pre-HAART era, patients with HIVAN typically presented with a nephrotic syndrome consisting of nephrotic-range proteinuria classically without oedema despite severe hypoalbuminaemia. Urinalysis reveals microhaematuria. Patients with HIVAN are typically not hypertensive, even in the face of renal insufficiency, and their kidneys are usually normal to large in size and highly echogenic by ultrasonography. The most common histological light microscopy finding is a collapsing form of focal segmental glomerulosclerosis. Tubulo-interstitial scarring, atrophy and marked dilatation of the tubules (microcystic dilatations) are usually present. Immunofluorescent microscopy is usually negative. Electron microscopy reveals wrinkling of the basement membranes, epithelial cell proliferation and focal foot process effacement. Tubulo-reticular structures in the glomerular endothelial cells consisting of ribonucleoprotein and membrane, the synthesis of which is stimulated by alpha-interferon, is highly predictive of HIVAN. Risk factors for progressive renal disease include CD4 cell count < 200 cells/μl, detectable plasma HIV RNA, hypertension, low plasma albumin and elevated serum creatinine [28]. In our experience during the HAART era, where most patients have well-controlled HIV, a nephropathy typically presents as stable or slowly progressive renal failure, hypertension, glomerular proteinuria, not necessarily of nephrotic range, and a preserved rather than increased kidney size. Pathologically, simple tuft ischaemia tends to replace florid (?) glomerular collapse while mild interstitial infiltration and cystic tubular dilatation are seen. Paradoxically, we noted more frequent atherosclerotic vascular changes even in younger affected patients. Until recently, the clinical course of HIVAN was one of inexorable progression to ESRD in 6–12 months, with limited treatment options. More options are now available to patients; these include antiretroviral therapy, steroid treatment and angiotensin-converting enzyme inhibitors. Evidence exists that antiretroviral therapy can reverse or improve the progression of HIVAN [15,16,19]; however despite the widespread use of HAART, no prospective studies have demonstrated benefit in slowing the progression of HIVAN. The survival benefit from antiretroviral therapy is indisputable. HAART may also prevent the development of HIVAN in at-risk groups. Lucas et al.[29] evaluated a cohort of 3976 at-risk patients in the Johns Hopkins HIV clinic database from 1989 to 2001. They identified 135 cases of HIVAN based on either clinical or pathological criteria. There was a 50% decline in HIVAN incidence in 1998–2001 compared with 1995–1997, and HAART was associated with a 60% reduction in risk for developing HIVAN. Patients with AIDS developed HIVAN at a rate of 12.5/1000 person-years, compared with 3.1/1000 person-years in patients without AIDS (relative risk, 4.1). However, it is notable that in over 1071 person-years of follow-up, no patient developed HIVAN when HAART was initiated prior to the onset of AIDS. The rationale for treating HIVAN with corticosteroids is that steroids are the mainstay of treatment for idiopathic focal segmental glomerulosclerosis [30]. The first report of steroid treatment in four patients with HIVAN found a significant reduction in serum creatinine after a course of corticosteroids lasting 2–4 weeks [31]. The initial case report study has now been extended to include 20 patients, and these results confirm that prednisone at a dose of 60 mg daily for 2–11 weeks leads to a significant reduction in serum creatinine and in 24-hour urinary protein excretion [30]. The encouraging short-term results must be balanced by the findings during the follow-up period. During a median follow-up of 44 weeks, 8 of 20 patients required maintenance dialysis, 11 of 20 died of HIV disease after completing prednisone treatment, and 6 of 20 developed serious infections while receiving prednisone. Only 7 of 20 patients were alive and free from ESRD after a median of 25 weeks following initiation of prednisone. A more recent retrospective study reported the course of HIVAN in 13 patients treated with prednisone and a further eight patients not treated with prednisone. Even after controlling for baseline creatinine, proteinuria, and CD4 cell count, among other variables, the prednisone group had an 80% reduction in risk of progressive azotaemia after 3 months [32]. Prednisone may work by reducing the amount of interstitial inflammation [33]. In 1995, The AIDS Clinical Trials Group (ACTG) designed a phase II randomized, double-blind, placebo-controlled multicentre trial to determine the efficacy of prednisone therapy in HIVAN, but this trial was cancelled because of poor patient recruitment. The angiotensin-converting enzyme inhibitors captopril and fosinopril have also been studied as possible therapy for HIVAN [34]. In one study in which 18 patients were enrolled, nine were treated with captopril, 6.5–25 mg three times daily, and nine controls did not receive captopril. All patients had biopsy-proven HIVAN, and renal survival was defined as the time from initiation of captopril treatment to initiation of dialysis (ESRD). The initial mean serum creatinine concentration was 34 mg/l (±7.0) in the captopril group and 37 mg/l (±0.5) in the controls. A small renal survival advantage of approximately 8 weeks (median 83 versus 30 days), was seen in the captopril group [35]. Two non-randomized studies have investigated the effect of fosinopril on the progression of HIVAN. Both studies showed a significantly lower risk of reaching ESRD in the fosinopril group compared with non-treated controls [35,36]. Despite the limitations of these studies, they suggest that therapy with an angiotensin-converting enzyme inhibitor initiated early may offer renal survival benefits in HIVAN. The ACTG is currently developing a clinical trial (protocol A5179) to compare treatment with an angiotensin receptor blocker (valsartan) plus HAART with HAART alone in patients with HIVAN. Indications for kidney biopsy The decision to obtain a renal biopsy sample is somewhat controversial in the general medical community. Even if a patient presents with the classic clinical features of HIVAN, clinical presentation is predictive of the biopsy diagnosis in only 50–60% of patients. Furthermore, non-invasive tests or clinical markers to identify the precise renal lesion do not exist. Renal biopsy should be offered to patients because a variety of renal lesions occur in HIV-infected patients, and the treatment implications and prognosis vary according to the biopsy results. We, therefore, believe that to distinguish HIVAN from other forms of renal disease, and to redefine HIVAN pathological findings in the HAART era, HIV-positive patients who have unexplained renal abnormalities (i.e., kidney failure and/or daily protein excretion greater than 1 g and/or microscopic haematuria) should have a renal biopsy. HAART-related kidney disorders Electrolyte and acid-base profiles It is noteworthy that the biological profile in HIV-infected patients has dramatically changed in the HAART era. Previous studies stated that hyponatraemia, hyperkalaemia or hypokalaemia and acidosis were the main biological abnormalities in HIV-positive patients [37,38]. A prospective cross-sectional descriptive study (1219 HIV-infected patients over 3 months) undertaken to assess the prevalence of fluid electrolyte and acid–base disturbances showed hyperuricaemia and hypophosphataemia to be the most prevalent abnormalities [39]. Hyperuricaemia was detected in 140 (41.3%) out of the 339 patients tested. Among hyperuricaemic patients, only 47% were treated with didanosine. Multivariate analysis showed that patients not taking non-nucleoside transcriptase inhibitors (NNRTI) had a 1.8-fold risk [95%confidenceinterval(CI),1.1–2.9] of hyperuricaemia. With protease inhibitor treatment and male gender, the risk of hyperuricaemia rose to 4.4 (95% CI, 2.1–9.6). A plasma phosphate level below the normal range was observed in 63 (17.2%) of the patients tested for plasma phosphate. Multivariate analysis showed that patients taking an NNRTI regimen had a 1.9-fold increase in risk of hypophosphataemia (95% CI, 1.1–3.3), male patients had a 2.6-fold increase in risk (95% CI, 1.1–6.3). Bicarbonate plasma level below the normal range was observed in 112 patients (13.6%) out of the 824 patients tested. Multivariate analysis showed that patients taking HAART had a 4.4-fold increase in risk having a low plasma bicarbonate level (95% CI, 2.2–8.9), women had a 2.4-fold increased risk (95% CI, 1.5–3.8) and patients with CD4 cell count < 200 cells/μl had a 1.8-fold increased risk (95% CI, 1.2–2.9). Only 13 patients (3.1%) out of the 419 patients tested exhibited low calcium levels (n = 13). Factors significantly associated with low plasma calcium concentrations were NNRTI regimen and CD4 cell count. An absolute CD4 count < 200 cells/μl was associated with an increased risk of hypocalcaemia when compared with a cont of > 200 cells/μl. Lactic acidosis Approximately 20–30% of patients who are treated with nucleoside reverse transcriptase inhibitors (NRTI) can be found to have asymptomatic hyperlactataemia; this typically develops after several months of therapy and may be transient [40–42]. Severe lactic acidosis is much rarer, occurring in 1.5–2.5% of patients, is usually preceded by fatigue, nausea, vomiting, anorexia, abdominal pain and other systemic symptoms, and is associated with a mortality rate of approximately 80%. Lipoatrophy, myopathy, peripheral neuropathy and pancreatitis are more often observed in patients with symptomatic hyperlactataemia rather than in patients who have frank lactic acidosis. Risk factors include NRTI use, longer duration of treatment, older age, female gender, pregnancy, hypertriglyceridaemia, obesity, concomitant hepatitis C infection, use of ribavirin, impaired kidney function and alcohol ingestion [41–44]. Acute renal failure Before the HAART era, mild acute renal failure, defined as a peak serum creatinine ≥ 20 mg/l, was been reported to occur in up to 20% of hospitalized HIV-infected patients [45]. This is in comparison with an incidence rate of 1% in hospitalized non-HIV-infected patients [46]. The two major acute renal complications in HIV disease that resulted in potentially reversible failure were acute tubular necrosis and HIVAN. Sepsis contributed to the development of severe acute tubular necrosis, defined as a peak creatinine ≥ 60 mg/l, in up to 75% of cases [47]. A study of kidney biopsy specimens in HIV-infected patients with severe acute renal failure not thought to be from prerenal causes or acute tubular necrosis reported the following distribution of renal lesions: 53% haemolytic uraemic syndrome; 40% acute tubular necrosis, either of ischaemic–toxic origin or rhabdomyolysis; 26% obstructive renal failure, extrinsic, drug induced or secondary to paraprotein precipitation; 23% HIVAN; 3% acute interstitial nephritis; and 6% various glomerulonephritides [48]. In a recent cohort study of ambulatory HIV-infected patients, acute renal failure occurred in nearly 10% of patients, with an incidence rate of 5.9 episodes/100 person-years [49] Antiretroviral agents have been shown to have a range of nephrotoxic effects, including crystal-induced obstruction, tubular toxicity, interstitial nephritis and electrolyte abnormalities. Drugs are responsible for one-third of all acute renal failure events. Although only responsible for a few events, antiretroviral drugs cause two-thirds of all obstructive acute renal failure. Indinavir, tenofovir, and nevirapine were the antiretroviral drugs associated with acute renal failure in this cohort [49–52]. Iatrogenic acute renal failure can be dose dependent, manifesting as acute tubular necrosis, acute glomerulopathy, vascular disease or interstitial immunoallergic reactions. Table 1 summarizes the nephrotoxicities induced by antiretroviral drugs [53–77]. According to the renal syndrome, the clinician will attempt to distinguish between possible causes from each of the four aetiopathogenic groups of nephropathies defined above. Depending on the situation, renal biopsy may be indicated. Table 2 proposes a diagnostic flowchart applicable for a HAART- treated patient with renal abnormalities.Table 1: Antiretroviral drug-induced renal abnormalities.Table 2: HIV-infected patients with renal abnormalities: a diagnosis proposition.Chronic renal failure Chronic renal abnormalities are frequently observed in HIV-infected individuals. Despite drug adjustment, some HIV-infected patients experience progressive renal disease. Usually, the diagnosis of renal toxicity of antiretroviral treatment is considered when patients experience acute renal abnormalities. However, the potential insidious long-term renal toxicity of antiviral treatment may be underappreciated in the pathogenesis of nephropathies of chronic progression in HIV infected patients. In prospective studies evaluating the safety and efficacy of the protease inhibitor indinavir, or some reverse transcriptase inhibitors, a of patients with acute renal failure did not their baseline renal function and data the of renal after acute renal related to antiretroviral the large range of kidney diseases that may occur in HIV-positive patients taking HAART, each case should be and the benefits and of drug The main for the clinician is to determine the of the nephropathy in order to specific in to symptomatic complications With the of HIV the complications associated with HIV infection have to include changes in HIV protease inhibitors and the to peripheral and impaired distribution elevated plasma and and elevated plasma have been reported in clinical trials and in changes in may be related to HIV disease or may be a of treatment with antiretroviral agents through in to long-term antiretroviral therapy the development of chronic kidney disease, through metabolic complications Indeed, black and have been associated with the development of Both protease inhibitors and NNRTI have been associated with and studies have shown plasma concentrations to be associated with increased mortality in in and/or older patients Evidence of hyperuricaemia in HIV-positive patients should to change in the of patients, as of The impact of and antiretroviral metabolic disorders on the of kidney or disease in patients with HIV therefore, an important Risk factors for nephrotoxicity renal adverse are not it is possible to identify patients who may be at increased risk factors for kidney disease, including older age, African-American comorbid and kidney disease, to be associated with renal failure in patients In addition, disease and hepatitis have been associated with increased risk for acute or chronic kidney disease in HIV-infected patients kidney function is one of the most of risk for acute or chronic kidney disease in patients The recently consensus guidelines for chronic kidney disease in all HIV-infected patients at the time of with frequent in the of kidney function or other evidence of kidney disease [24]. Initial should include and serum creatinine with of the glomerular rate by either the or of in Renal Disease has been in patients with HIV, are more than serum creatinine of patients with a glomerular rate < 60 will for dose of by the and should more frequent of kidney toxicity and The according to the glomerular rate and the of dose for each are in Table The of proteinuria by or also chronic kidney disease, and may identify patients at increased risk for nephrotoxicity [24]. In to chronic kidney disease, other factors as and concomitant of other nephrotoxic agents may also patients to the nephrotoxic effects of HAART or related HAART can also to Indeed, studies over the past 20 in patient have demonstrated a between in disease and et found a increase in the risk of developing elevated among patients receiving compared with receiving In addition, the results suggested that the increased risk associated with was at least in part, through an increase in Antiretroviral dose based on creatinine with HIV and hepatitis or C The effect of with hepatitis in and C on disease progression and survival among patients infected with HIV has an increasing this has from the effects of while this function and decreases the incidence of infections in HIV-infected patients, it also the of chronic disease to the overall and mortality of these individuals. use of alcohol is an in this Approximately of HIV-infected patients are Among intravenous drug with HIV, this rate is at least 50% and can be up to 90% in with and HIV is with of HIV-infected individuals having evidence of past or infection The prevalence of chronic of among HIV-infected individuals is Among intravenous drug 90% of HIV-infected individuals have evidence of to and 60% also have evidence of past infection with the of of renal disorders has not been reported in However, proteinuria and have been reported frequently in or patients without HIV proteinuria to and in infected patients; proteinuria to 30% and 30% in patients. has been in and patients and is characterized by and peripheral neuropathy The renal presentation of in patients may include renal insufficiency, proteinuria, and The course of renal disease is much more in the with some to ESRD in a of months However, while reports had shown between HIV and with et did not an between HIV infection and In patients not with HIV, the of nephropathy with and has also been and the reports of nephropathy in HIV-infected patients may be by the incidence of infection, and in this population The life expectancy of HIV-positive patients treated with HAART now that of the general The has to the and renal that can increase with more in patients hypertensive, 2 and risk factors to renal disorders from HIV infection and HAART. it more important to develop for treating these patients from the renal Renal to be in patients with HIV/AIDS and potentially reversible factors to be identified and the we suggest the antiretroviral drug use and kidney disease in HIV-infected patients. All patients at the time of HIV diagnosis should be for kidney disease with a for proteinuria and a of renal is no evidence of proteinuria at initial patients at risk for the development of renal disease (i.e., African-Americans, with CD4 cell < 200 cells/μl or plasma HIV > and with hypertension, or should Renal function should be on a to assess for changes over proteinuria, renal renal biopsy. Patients with glomerular rate 60 or with proteinuria > by or on should be to a for further evaluation and In HIV-infected patients with evidence of should be controlled to a level no than enzyme inhibitors or angiotensin receptor are the drugs of first for patients with proteinuria, and these drugs should also be considered in HIV-infected patients with renal disease. should be in patients receiving protease inhibitors. Patients with HIVAN should be treated with HAART at HAART should not be from patients because of the of their renal The antiretroviral regimen is a between the benefits of and the risk of adverse events, including The of renal insufficiency should the and dose of the antiretroviral of prednisone should be considered in patients with HIVAN if HAART alone not result in improvement of renal function or in patients with HIVAN renal failure is A that the of short-term the benefit of slowing the progression to ESRD and the should the decision reduction of for antiretroviral drugs that are the kidneys is With dose and renal insufficiency or ESRD is not an absolute to the use of any antiretroviral nucleoside should not be in patients with renal function for of the development of lactic acidosis. Drugs that are by dialysis should be after to of In HIV-positive renal are important between the inhibitors and protease inhibitors, and the NNRTI drug may increase levels of and tenofovir, their In the of protease inhibitors, a major reduction in the of inhibitors may be Although most antiretroviral agents are free of renal toxicity, renal can occur and may to be from progression of HIVAN or other HIV-related kidney kidney diseases by other infections or or kidney diseases to HIV infection and its and diseases have emerged as important complications in patients, infections as causes of among HIV-infected patients. patients with risk or a history of a consideration should be to or to protease antiretroviral with the use of NRTI or NRTI and and between disease and will diagnosis and treatment of chronic kidney and vascular diseases with the of progression to ESRD. The authors and for their The authors in the had to all the data in the study and had for the decision to to

Medical Nutrition Therapy for Patients with Non–Dialysis-Dependent Chronic Kidney Disease: Barriers and Solutions

The Third World Kidney Day: Looking Back and Thinking Forward

Person-Centered Kidney Education: The Path Forward

Unleashing the Power of Renal Nutrition in Value-Based Models of Kidney Care Choices: Leveraging Dietitians’ Expertise and Medical Nutrition Therapy to Delay Dialysis Initiation

The prevalence of HIV-associated chronic kidney disease (CKD) varies geographically and depends on the definition of CKD used, ranging from 4.7% to 38% globally. The incidence, however, has decreased with the use of effective combined antiretroviral therapy (cART). A wide variety of histological patterns are seen in HIV-associated kidney diseases that include glomerular and tubulointerstitial pathology. In resource-rich settings, there has been a plateau in the incidence of end-stage renal disease secondary to HIV-associated nephropathy (HIVAN). However, the prevalence of end-stage renal disease in HIV-positive individuals has risen, mainly due to increased longevity on cART. There is a disparity in the occurrence of HIVAN among HIV-positive individuals such that there is an 18- to 50-fold increased risk of developing kidney disease among HIV-positive individuals of African descent aged between 20 and 64 years and who have a poorer prognosis compared with their European descent counterparts, suggesting that genetic factors play a vital role. Other risk factors include male sex, low CD4 counts, and high viral load. Improvement in renal function has been observed after initiation of cART in patients with HIV-associated CKD. Treatment with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker is recommended, when clinically indicated in patients with confirmed or suspected HIVAN or clinically significant albuminuria. Other standard management approaches for patients with CKD are recommended. These include addressing other cardiovascular risk factors (appropriate use of statins and aspirin, weight loss, cessation of smoking), avoidance of nephrotoxins, and management of serum bicarbonate and uric acid, anemia, calcium, and phosphate abnormalities. Early diagnosis of kidney disease by screening of HIV-positive individuals for the presence of kidney disease is critical for the optimal management of these patients. Screening for the presence of kidney disease upon detection of HIV infection and annually thereafter in high-risk populations is recommended.

Urate-Lowering Therapy for Preventing Kidney Disease Progression: Are We There Yet?

In the era of widespread use of antiretroviral therapy (ART), people with HIV (PWH) have a near-normal life expectancy. However, PWH have high rates of kidney diseases and progression to end-stage renal disease at a younger age. PWH have multiple risks for developing acute and chronic kidney diseases, including traditional risk factors such as diabetes, hypertension, and HIV-related factors such as HIV-associated nephropathy and increased susceptibility to infections and exposure to nephrotoxic medications. Despite an improvement in access to kidney transplant among PWH, the number of PWH on dialysis continues to increase. The expansion of the number of antiretrovirals (ARVs) and kidney replacement modalities, the absence of pharmacokinetic data, and therapeutic drug monitoring make it very challenging for providers to dose ARVs appropriately leading to medication errors, adverse events, and higher mortality. Most of the recommendations are either based on small sample size studies or extrapolated based on physiochemical characteristics of ART. We aim to review the most available and most current literature on ART in PWH with renal insufficiency and ART dosing recommendations on dialysis to ensure that PWH are provided with the safest and most effective ART regimen.

Chronic kidney disease (CKD) is a major health and economic burden within Australia. Estimated glomerular filtration rate (eGFR) and albuminuria (Alb) are used to determine if a patient has CKD, but these routine clinical kidney function measurements are inadequate when predicting progressive CKD. This thesis addressed two themes: firstly, clinical CKD biobanking within Australia; and secondly, improving clinical and research outcomes for CKD patients by developing a prognostic clinical tool.Four aims were completed. i) To establish a clinical biobank, termed the CKD Biobank, within Queensland, Australia and develop this into a bioresource. 100 CKD patients, consisting of patients with diabetic nephropathy, vascular diseases, genetic kidney diseases, glomerulonephritis, and a range of other primary kidney diseases, were recruited. In approximately 80% of these patients, baseline bio-specimens were collected alongside clinical data.ii) To address the need for a better definition of progressive CKD and to identify a robust definition of progressive kidney function decline. A systematic review was conducted to identify definitions of progressive kidney function decline currently used in research. A range of definitions was identified and subsequently investigated within the CKD Queensland Registry. A ≥30% decline in eGFR from baseline was found to be robust in distinguishing between patients who experienced a progressive decline in kidney function and those who did not.iii) To use the CKD Queensland Registry and CKD Biobank to identify biomarkers of progressive CKD. Discovery-based and hypothesis-based approaches were used, within the CKD Queensland Registry and the CKD Biobank, respectively, to identify novel and emerging biomarkers of progressive CKD. Several biomarkers were identified that characterised the pathophysiological mechanisms of CKD, with varying capacity to distinguish between progressive and non-progressive CKD.iv) To develop a novel prognostic clinical tool, termed the “distinguishing risk of progressive CKD” (DROP CKD) tool, for differentiating between progressive and non-progressive CKD patients at baseline biomarker measurements. The DROP CKD tool was a predictive model calculated by linear discriminant analysis and constructed from biomarkers that differed between progressive and non-progressive CKD patients. A step-backwards approach was used for biomarker selection to maximise accuracy of the DROP CKD tool.Three hypotheses were investigated. i) A biobank, designed for a specific application that overcomes the ethics, governance, and quality control hurdles, will prove a valuable bioresource. The CKD Biobank has proved a useful bioresource, not only for this thesis, but for several other research projects. The CKD Biobank was utilised for investigating progressive CKD biomarkers and developing the DROP CKD tool for predicting progressive CKD. This Biobank was used, additionally, to supply bio-specimens from healthy controls for a discovery-based project to identify metabolites with prognostic capabilities in kidney cancer, and bio-specimens from diabetic nephropathy and glomerulonephritis CKD patients for research concerning presence of coagulation proteases in urine.ii) Progressive and non-progressive CKD will be characterised by biomarkers of kidney function, tissue injury, inflammation, oxidative stress, tissue repair, fibrosis, and comorbidities of CKD within the venous blood or urine of CKD patients. Compared to non-progressive patients, progressive patients of the CKD Queensland Registry and the CKD Biobank were characterised as having reduced kidney function, being anaemic, having an altered electrolyte-water balance, metabolic acidosis, dyslipidaemia, and as having mineral and bone disease. Progressive CKD patients of the CKD Biobank were further characterised by tissue injury, inflammation, and hypercoagulability while progressive CKD patients of the CKD Queensland Registry were only additionally characterised by eosinophilia.iii) A panel of the biomarkers, measured at baseline, will accurately predict progressive CKD. Biomarkers that were observed as differing between progressive and non-progressive CKD patients of the CKD Biobank were utilised to develop the DROP CKD tool. Through the step-backwards method, a biomarker panel consisting of eGFR, serum creatinine, cystatin-c, urea, tumour necrosis factor (TNF)-α, TNF Receptor-I, TNF Receptor-II, stem cell factor, tryptase, neutrophil gelatinase-associated lipocalin, tissue factor, bicarbonate, calculated osmolality, and haematocrit were observed as having an accuracy of 95.5% when predicting progressive CKD based on baseline biomarker expression. Moreover, the DROP CKD tool was more accurate than traditional kidney function measurements for determining progressive CKD.This thesis attempted to expand upon CKD biobanking capabilities and improve clinical and research outcomes for CKD patients by developing a novel prognostic clinical tool for predicting progression of CKD. Several avenues of research are still required to produce translatable results that will improve patient outcomes. Defining progressive CKD requires further investigation to identify a definition that robustly characterises a “progressive” decline in kidney function, accounting for the non-linear nature of eGFR decline and associating with meaningful clinical outcomes without underdiagnosing progression. Additional biomarker discovery is needed to identify novel biomarkers which can characterise progressive CKD. Finally, pre-existing and novel biomarkers need to be combined into a panel that can predict progressive CKD. This panel must be assayed in a minimally-invasive, efficient, manner, and communicate clinically-meaningful information to inform clinical management of CKD patients.

Does Kidney Longevity Mean Healthy Vegan Food and Less Meat or Is Any Low-Protein Diet Good Enough?

Practice NursingVol. 22, No. 4 Clinical Renal DiseaseChronic kidney disease in the primary care settingFiona MurphyFiona MurphySearch for more papers by this authorFiona MurphyPublished Online:29 Sep 2013https://doi.org/10.12968/pnur.2011.22.4.184AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View articleReferencesAdil M, Aslam S (2009) Prevention of progression of chronic kidney disease and its cardiovascular complications. In: Wilcox CS, Tisher CC, eds. (2009) Handbook of Nephrology and Hypertension. 6th edn. Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia: PA Google ScholarDepartment of Health (2005) National Service Framework for Renal Services. Part Two: Chronic kidney disease, acute renal failure and end of life Care. http://tiny.cc/ztd61 (accessed 14 March 2011) Google ScholarLevey AS, Coresh J, Greene Tet al. (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145(4): 247–54 Crossref, Google ScholarMacGregor MS, Taal M W (2011) Detection, Monitoring and Care of Patients with Chronic Kidney Disease. Final Draft. UK Renal Association Clinical Practice Guidelines. 5th edn. http://tiny.cc/y9vkv (accessed 14 March 2011) Google ScholarMartin S. (2011) World Kidney Day 2011: Protect Your Kidneys, Save Your Heart. Am J Kid Dis 57(3): 371–4 Crossref, Google ScholarMobley A (2009) Slowing the progression of chronic kidney disease. The Journal for Nurs Practitioners 5(3): 188–94 Crossref, Google ScholarMurphy F, Bennett L, Jenkins K. (2010) Managing anaemia of chronic kidney disease. Br J Nurs 19(20): 1281–6 Link, Google ScholarMurphy F, Jenkins K, Chamney Met al. (2008a) Patient Management in CKD Stages 1 to 3. J Ren Care 34(3): 127–35 Crossref, Google ScholarMurphy F, Jenkins K, McCann Met al. (2008b) Patient Management in CKD Stages 4 to 5. J Ren Care 34(4): 191–8 Crossref, Google ScholarNational Collaborating Centre for Chronic Conditions (2008) Chronic Kidney Disease. Early Identification and Management in Adults in Primary and Secondary Care. Clinical guideline 73. http://tiny.cc/69tvq (accessed 15 March 2011) Google ScholarNHS Information Centre (2009) QOF prevalence data. http://tiny.cc/l351k (accessed 15 March 2011) Google ScholarNational Institute for Health and Clinical Excellence (2006) Hypertension: Management of Hypertension in Adults in Primary Care. Clinical guideline 34. http://www.nice.org.uk/CG034 (accessed 16 March 2011) Google ScholarNational Kidney Federation Kidney Dialysis Outcome Quality Initiative (2002) Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. http://tiny.cc/p0in0 (accessed 16 March 2011) Google ScholarNational Kidney Federation Kidney Dialysis Outcome Quality Initiative (2007) Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes for Chronic Kidney Disease. Am J Kidney Dis 49(2; Suppl 2): S12–154 Crossref, Google ScholarScottish Intercollegiate Guidelines Network (SIGN) (2008) Diagnosis and Management of Chronic Kidney Disease. A National Clinical Guideline. http://tiny.cc/b0pcd (accessed 17 March 2011) Google ScholarThomas N (2007) Recent developments in the care and management of chronic kidney disease. Prim Health Care 17(6): 41–5 Crossref, Google ScholarThomas N (2011) The management of chronic kidney disease. Nurs Prescribing 9(2): 76–81 Link, Google ScholarWorld Health Organization (2008) WHO 2008–13 action plan for the global strategy for the prevention and control of non communicable diseases. http://tiny.cc/ua93e (accessed 16 March 2011) Google Scholar FiguresReferencesRelatedDetailsCited ByManaging post-transplant patients in primary care29 September 2013 | Practice Nursing, Vol. 22, No. 6 1 April 2011Volume 22Issue 4ISSN (print): 0964-9271ISSN (online): 2052-2940 Metrics Downloaded 15 times History Received 22 March 2011 Accepted 24 March 2011 Published online 29 September 2013 Published in print 1 April 2011 Information© MA Healthcare LimitedKeywordsChronic kidney diseaseprimary carepreventionmanagementPDF download