#34234: Renal Disease and Failure

Renal disease is a serious health issue, affecting an ever-increasing number of patients and resulting in substantial financial costs in the United States. The total investment in kidney-related research across the entire National Institutes of Health is estimated to be $704 million in 2024 [1]. In 2021, the Medicare program spent $67,993 per person per year for the care of patients with end-stage kidney failure[2]. Renal disease demands the involvement of many other healthcare personnel, including mental health professionals. Renal disease generally falls into one of two categories: chronic kidney disease (CKD) or acute kidney injury (AKI) [3,4].

CKD is defined as a reduction in kidney function or kidney damage that has been present for at least three months [3,4,5,6]. However, CKD should not be viewed in simple mathematic terms. It is an ongoing process of renal injury that causes compensatory hyperfiltration in less-affected glomeruli, which eventually leads to the destruction of those glomeruli as well [3]. Left untreated, this ongoing destruction results in a steady decline in renal function, which eventually affects not just the renal system but almost every organ system in the body [3,4].

AKI is defined as an increase in serum creatinine of 0.3 mg/dL or more within 48 hours; or an increase in serum creatinine of more than 1.5 times the baseline within the prior 7 days; or urine volume less than 0.5 mL/kg/hour for 6 hours. AKI may be classified either by the physiologic cause (i.e., prerenal, intrarenal, or postrenal) or by the amount of urine produced (i.e., anuric, oliguric, or nonoliguric) [7,8].

The term end-stage renal disease (ESRD) refers to disease that requires either dialysis or transplantation services. In the United States, 98% of all patients receiving dialysis or transplantation have a glomerular filtration rate (GFR) <15 mL/min/1.73 m²[9]. Therefore, the terms ESRD and kidney failure are often used interchangeably. Although ESRD is generally associated with a GFR less than 15 mL/min/1.73 m², it is more importantly an administrative term, as patients receiving dialysis or transplantation services are covered by the Medicare ESRD program [10]. In some cases, ESRD is also used rather loosely to refer to patients who are experiencing progressive CKD and are expected to begin dialysis in a matter of days or weeks.

Practice guidelines published by the National Kidney Foundation (NKF) and the Kidney Disease: Improving Global Outcomes (KDIGO) Network define and classify CKD based on GFR category [6,9]. KDIGO guidelines also include the identification of cause and albuminuria category in its classification system [6]. These staging systems are used to predict CKD progression and associated complications (Table 1), with an emphasis on predicting the development of cardiovascular disease, the leading cause of death in patients with ESRD and the cause of dramatically increased mortality rates in patients with even moderate kidney disease. Identifying and staging patients with impaired renal function is important in order to prevent or slow the onset of CKD and its complications.

A common marker of CKD is proteinuria, which is first detectable as microalbuminuria (i.e., >30 mg albumin in a 24-hour urine collection). Due to the difficulty of measuring 24-hour urine protein excretion, proteinuria is usually screened using dipstick or a spot urine albumin-creatinine ratio. Other indicators include abnormal urine sediment or abnormal imaging studies.

GFR is the best measure of kidney function. Normal adult GFR is 120–130 mL/min/1.73 m², but it declines naturally with age. Definitions of CKD are not age-adjusted, and therefore the prevalence of CKD increases with age.

True determination of GFR is made by collecting urine for 24 hours in tandem with a serum creatinine measurement. Patient compliance with urine collection can prove quite difficult and 24 hours may be too long to wait, so many clinicians rely on indirect calculators such as the estimated GFR (eGFR), which determines GFR based on numerous biomarkers including serum creatinine [6].

Although exact statistics regarding the prevalence of mild-to-moderate renal failure are not available, the epidemiology of ESRD has been widely documented by the U.S. Renal Data System (USRDS), which collects statistics on all Medicare patients on dialysis. Since 1974, Medicare coverage has been extended to virtually all patients on dialysis in the United States; therefore, these data are highly representative of the current dialysis population. According to the USRDS, the number of patients with ESRD in the United States was 807,337 in 2019, an increase of 88.2% since 2002 [11]. Among patients with incident ESRD in 2021, 7.9% were waitlisted prior to ESRD onset or received a kidney transplant as their initial ESRD treatment modality. Although this percentage was relatively low, it represents an increase from 6.4% in 2011 [11].

The two leading causes of ESRD are diabetes (38% of new patients) and hypertension (27% of new cases) [12]. New cases of ESRD with diabetes or hypertension listed as the primary cause had been rising rapidly since 1980, but each has declined from 2000 to 2016 [13,14]. Other less common causes of ESRD include glomerulonephritis, interstitial nephritis, autosomal dominant polycystic kidney disease (the leading genetic cause), and collagen vascular disease. Due to the prevalence of kidney transplantation, post-transplantation kidney disease has become the fourth largest cause of ESRD in the United States; however, these patients are reported within their original disease category for epidemiologic purposes [15]. New cases of diabetic ESRD are expectedly higher with increasing age in all racial groups, but generally lower among younger individuals [11]. Statistically, non-whites are four times more likely to require dialysis. Adjusted ESRD prevalence increases with advancing age, with 7,048 cases per million people 65 to 74 years of age and 7,380cases per million people 75 years of age and older. Adjusted ESRD prevalence in Black, White, and Asian individuals was essentially unchanged between 2021 and 2022. However, adjusted ESRD prevalence in Black Americans was 23 times higher than in White Americans in 2022; 14 years earlier, that ratio was 3.8, highlighting the slow progress in addressing the disparity in ESRD prevalence [11].

AKI is primarily a disease of hospitalized patients and often is the result of pre-existing chronic kidney disease [11]. The adjusted rate of first hospitalization with AKI during a year among Medicare fee-for-service beneficiaries increased by approximately 32% over 10 years, from 32.5 admissions per 1,000 person-years in 2012 to 42.7 admissions per 1,000 person-years in 2022 [11]. AKI rates are significantly associated with aging and with white race [11]. The most common causes of AKI vary according to pathophysiology, but possible etiologies include trauma, dehydration/volume depletion, tubulointerstitial disease, glomerulonephritis, and obstruction [3,8].

The basic pathophysiology of CKD is that of renal injury and loss of functioning nephrons, the mechanism of which depends on the underlying cause. The result is hyperfiltration in the surviving glomeruli (in an attempt by the body to increase GFR), which then causes ongoing glomerular stress, renal injury, and eventually glomerular destruction [3,5]. This leads to a decrease in GFR and a continuance of the hyperperfusion destruction syndrome. Allowed to continue, the patient will inevitably develop ESRD and require dialysis or transplantation to avoid death from uremia. When treatment to reverse this process is initiated prior to the patient losing more than 40% to 50% of renal function, stabilization is possible. After a patient has lost more than 50% to 60% of renal function, failure is considered inevitable.

The pathophysiology of AKI depends on the site of occurrence. Prerenal AKI, the most common type, is caused by renal hypoperfusion (most likely from dehydration) [16]. Intrarenal or intrinsic AKI, the result of damage to the renal parenchyma, may be a result of prolonged prerenal AKI (leading to acute tubular necrosis), toxins, interstitial disease, vascular disease, or acute glomerular disease [16]. Postrenal (obstructive) AKI results from physical obstruction of urine outflow and may be caused by neoplasm, prostatic enlargement, bladder dysfunction, or nephrolithiasis [3,16,17].

The clinical presentation of CKD is often subtle, and symptoms are uncommon with a GFR greater than about 35 mL/min/1.73 m². Therefore, suspicion for mild renal disease should be based on recognition of the primary pathologic mechanism responsible for renal injury, particularly in patients with diabetes and/or hypertension. It is equally important to begin early screening for the complications of renal disease to prevent morbidity and to establish a credible baseline for the individual patient.

After the GFR falls to less than 35 mL/min/1.73 m², a variety of metabolic, psychiatric, hematologic, cardiovascular, and acid-base regulatory problems occur (Table 2). Clinical presentation at this point depends on the particular complication and the underlying cause of renal failure [3,4,5,17,18].

The usual clinical presentation of AKI includes signs and symptoms of accumulation of nitrogen in the blood, such as fatigue, headache, anorexia, nausea, and vomiting. Potassium imbalances can result in tachycardia. Patients at highest risk for prerenal AKI have pre-existing CKD, have recently undergone surgery, been exposed to radiocontrast dye, have received aminoglycoside antibiotics, or have developed sepsis [8]. Postrenal AKI is associated with flank or abdominal pain and possibly neurologic symptoms. Most patients with AKI have identifiable risk factors, such as CKD, advanced age, liver disease, diabetes, or vascular disease [8]. Therefore, it is possible and essential to identify those at high risk before AKI develops in order to minimize damage.

The physical examination of patients with suspected renal disease or failure should include both a focused examination to identify pathologic processes caused by the primary disease entity (e.g., diabetes or hypertension) and a broader examination to identify the effects of progressive renal failure. Areas of importance include assessment of vital signs (including measurement of bilateral and orthostatic blood pressure); funduscopic evaluation for signs of arteriovenous (AV) nicking, diabetic retinopathy, and papilledema; assessment of volume status by determination of jugular vein distention; auscultation of lung sounds; assessment for edema or ascites; and assessment of heart sounds to screen for volume overload and pericarditis. A full abdominal examination is also recommended and should include auscultation for renal artery bruits; examination of the skin for ecchymosis, rashes (especially those suggesting collagen vascular disorders), or uremic frost (although this would indicate extremely advanced disease); percussion of the bladder to exclude distention; rectal examination; and evaluation of the prostate in male patients to exclude obstruction [17]. Formal and informal mental status examinations should be included to screen for depression, confusion, delirium, and other psychiatric complications.

The most important tool in monitoring patients with suspected and diagnosed renal failure or those at risk for developing renal disease is dipstick urinalysis, which should be performed at virtually every office visit. Urine dipstick testing is highly specific (although false positives do occur) but less sensitive than quantitative testing. The presence of proteinuria should alert the clinician to perform a full 24-hour urine analysis for protein and creatinine clearance (Table 3). All patients with diabetes who are negative for macroscopic proteinuria on dipstick testing should have laboratory testing for microalbuminuria, as early identification and treatment can improve prognosis. This testing should be initiated at the time of diagnosis for patients with type 2 diabetes and within two years of diagnosis for patients with type 1 diabetes [19].

The importance of dipstick testing in high-risk individuals, especially African Americans, diabetics, and hypertensives, cannot be overstated. Many institutions rely on serum creatinine measurements to identify renal disease. However, serum creatinine is not sufficiently sensitive for renal disease, with levels failing to rise above normal until the patient's GFR is less than 60 mL/min/1.73 m² and the progression to ESRD has already become inevitable [20]. Other biomarkers have been identified, including serum cystatin C and creatinine clearance and may be used in addition to GFR to identify the presence of renal disease [6,21]. Novel biomarkers specific to AKI may be useful, as these cases have generally been diagnosed using serum creatinine in the past due to the unreliability of GFR measurements [20,22,23,24,25]. Overall, early monitoring, early intervention, and tight control of modifiable risk factors could help many patients avoid the progression to ESRD.

After a patient has been diagnosed with renal disease, a baseline should be established by obtaining (in addition to the urinalysis) a full chemistry panel, including electrolytes, fasting blood glucose, magnesium, phosphorus, ionized calcium, total serum protein, serum albumin, blood urea nitrogen (BUN), creatinine, liver enzymes, lipid profile, complete blood count (CBC), and intact parathyroid hormone (iPTH) [21]. In addition, hepatitis B and C and HIV serology should be obtained [21].

In some patients, renal biopsy and nuclear imaging may be helpful [21]. However, the risks associated with invasive tests or exposure to contrast dye compels consultation with a nephrologist before subjecting the patient to potential complications. Although imaging studies are not particularly useful in diagnosing the extent of renal disease, renal ultrasound is recommended to determine the presence of cysts or obstruction and to document the size of the kidneys [17,18,21]. This is necessary, as CKD characteristically results in smaller than average kidneys, whereas AKI is characterized by normal or even enlarged kidneys. Asymmetry may be a result of unilateral renal artery stenosis.

The main issue in the diagnosis of CKD is exclusion of AKI. AKI is a potentially reversible, life-threatening condition, and all patients with AKI should be hospitalized. As noted, the most common type of AKI seen in primary care is prerenal AKI (caused by renal hypoperfusion) related to volume depletion or hypotension related to pre-existing risk factors, such as CKD, advanced age, liver disease, diabetes, or vascular disease [8]. Some patients with CKD have a small degree of reversible prerenal AKI caused by hypovolemia or alterations in renal hemodynamics that result in renal hypoperfusion (e.g., from nonsteroidal anti-inflammatory drugs [NSAIDs] or angiotensin-converting enzyme [ACE] inhibitors) [8].

Urinalysis is highly diagnostic in differentiating between AKI and CKD. Prerenal AKI is usually accompanied by urine osmolality of more than 500 mOsm/kg, specific gravity of more than 1.020, and hyaline casts. Intrarenal AKI results in a urine osmolality of approximately 300 mOsm/kg, with a specific gravity of around 1.010, tubular casts, tubular cells, and a distinctive brownish, muddy appearance of the urine due to brown granular casts [18,26].

Occasionally, outpatients may be seen with postrenal obstructive AKI. A distended bladder, flank pain, and prostatic enlargement are potential signs. Ultrasound imaging virtually always detects obstruction in these patients [18].

If, after a thorough history and physical examination, AKI is still considered a potential diagnosis, the patient should be urgently referred to a renal specialist. Renal ultrasound evaluation or biopsy may be necessary for a definitive diagnosis.

Vigilance is necessary to determine any underlying correctable pathologic process that may be causing renal failure. Renal vascular hypertension should always be considered when renal function deteriorates rapidly with the initiation of ACE inhibitors or when abdominal bruits are heard on auscultation.

Almost all patients with stage 1 and stage 2 CKD are managed in primary care. Stage 1 CKD is kidney disease with normal kidney function. Kidney function in stage 2 is 60% to 90% [27]. The emphasis for these patients is identifying and managing risk factors, monitoring progression of renal impairment, and beginning patient education. It is important to remember that the risk of cardiovascular events is higher in patients with early CKD than advancement to dialysis or kidney transplantation [27]. Therefore, interventions to address cardiovascular risk factors are warranted, including increased physical activity, dietary changes, smoking cessation, and possibly pharmacologic treatment of hyperlipidemia or hypertension. Factors that indicate an increased risk of advancement to higher stages of kidney disease include [27]:

When GFR falls to less than 20 mL/min/1.73 m², the progression to ESRD is virtually inevitable [31]. Because prevention of progression is improbable, the focus of management switches to prevention of complications. Although continued control of complications and metabolic/dietary concerns is important, the goals become more difficult as the GFR approaches 10 mL/min/1.73 m². Consultation with a renal specialist is imperative for proper care and planning at this point, and ideally, a relationship will have already been established.

ESRD is commonly defined as a GFR of less than 15 mL/min/1.73 m², and the basic hallmark of ESRD is uremia [5,88]. Uremic toxins are the byproducts of protein metabolism; in patients with ESRD, the toxins are not eliminated by the kidneys and begin to accumulate [5]. Severe uremia necessitates the use of dialysis to remove uremic toxins and prevent or control complications.

Symptoms of uremia affect virtually all major body systems and can include drowsiness, obtundation (that can evolve into coma), peripheral neuropathy, restless legs syndrome, atherosclerosis, cardiomyopathy, pulmonary edema, pneumonitis, anorexia, enterocolitis, pancreatitis, ascites, pruritus, anemia, platelet dysfunction, insulin resistance, and hyperlipidemia [5]. BUN levels are markers of uremia. Normal BUN levels range from 7–20 mg/dL. In patients with ESRD, BUN may rise to levels greater than 100 mg/dL. The most useful BUN measurement is the ratio of BUN to serum creatinine, which in healthy patients ranges from 0.5–1.2 mg/dL, dependent on muscle mass. Therefore, the normal BUN to serum creatinine ratio is 20:1. Higher ratios reflect dehydration. However, initiation of dialysis should be guided not just by laboratory values but also by clinical presentation. The presence of uremic symptoms in the patient, especially sleepiness and changes in mental status or serious complications such as pancreatitis or pulmonary edema, should be a major consideration when making treatment choices [88].

All patients with CKD should be referred as early as possible to a renal specialist for consultation. If a dietitian is available, referral should be made as well. Hospitalization should be considered for any acute, life-threatening disorder or complication. More common causes include acute fluid and electrolyte disorders, acute hypertensive emergency, pulmonary edema, acute CHF, pericarditis, and metabolic acidosis.

The basis for dialysis was not established until the discovery of diffusion and osmosis in the 1800s. This early form of chemical dialysis was initially used only in laboratories to separate chemical compounds. Thomas Graham and Adolf Fick established some of the first formal chemical procedures for separating chemical substances using diffusion across semipermeable membranes to separate dissolved substances. The formal theoretical foundation for dialysis was established by Albert Einstein when he described diffusion laws deriving from thermodynamics and Brownian molecular motion [5,93].

Hemodialysis uses an extracorporeal semipermeable membrane to separate uremic substances from the blood of patients suffering from kidney disease. The first known occurrence of the use of an extracorporeal filter was in 1913 on anesthetized animals [5,93]. Although crude, this technique of extracorporeal filtration remains the basis for current hemodialysis. The first human experiments were performed in Germany by George Haas in 1924. None of his patients survived, but all were in critical condition and were not expected to survive at the time of the procedure. One of the major contributions of Haas' experiments was the introduction of heparin as the anticoagulant of choice to prevent clotting in the filter mechanism; previous experiments had used a leech-based derivative [5,93].

The first successful hemodialysis on a living patient was accomplished by Willem Kolff in 1945 in the Netherlands. After 16 failures, he successfully dialyzed a woman 67 years of age suffering from acute renal failure using a rotating drum artificial kidney [5,93].

Although approximately 84% of patients on dialysis in the United States receive hemodialysis, peritoneal dialysis is also an option, and in some countries (including Mexico, New Zealand, and Australia), it is the major form of outpatient dialysis [94]. The decision to implement peritoneal dialysis rather than hemodialysis can be affected by many nonclinical factors, such as reimbursement, government policies, physician preference, and available expertise [5,11,65].

The first known clinical use of peritoneal dialysis occurred in 1923, and by 1950, at least 100 patients had been treated, most of whom were in acute failure. Of these patients, 32 successfully regained normal function [5]. However, continuous ambulatory peritoneal dialysis was not formally described until 1976. In continuous ambulatory peritoneal dialysis, the peritoneum acts as the semipermeable membrane and dialysis fluid is introduced via a permanent catheter, with old fluid removed and new fluid introduced either automatically during the night via an automated system (continuous cycler-assisted peritoneal dialysis) or manually up to four times per day (continuous ambulatory peritoneal dialysis) [65].

Peritoneal dialysis differs from hemodialysis in several ways. First, the membrane itself is not customizable; the patient's peritoneum is genetically determined. Secondly, the catheter transverses both a nonsterile (exterior abdomen) and sterile (peritoneum) environment. Thirdly, peritoneal dialysis solutions must be delivered to the home and used by patients and families. These difficulties have historically resulted in a relatively low rate of peritoneal dialysis use in the United States [5,65].

Use of home dialysis was 0.4% in 2021 and has been relatively stable since 2001 In 2021, use of peritoneal dialysis was 37.8% higher than in 2001 [11]. Peritoneal dialysis has continued to be the dominant form of home dialysis. As stated, approximately 83.8% of patients on dialysis in the United States continue to be treated by in-center hemodialysis [11]. This results in many nephrologists having little experience with peritoneal dialysis, creating a difficult-to-break cycle of lack of use due to lack of experience.

Hemodialysis is a risk factor for a variety of complications, and patients must be closely monitored. Mortality rates for patients with ESRD are high in part due to uncontrolled complications associated with dialysis.

Patients on hemodialysis often experience hypotension during and after dialysis sessions. A fluid gain of 4 or more liters between sessions is not uncommon, and this same amount of fluid must then be removed over a four-hour dialysis session. Most of this fluid is situated in the extravascular space, and dialysis removes fluid only from the intravascular space. So, changes in osmotic pressure between the intravascular and extravascular must allow for fluid movement during dialysis. If the patient becomes acutely hypotensive, the dialysis may need to be interrupted and the patient placed in Trendelenburg (supine) position with elevated feet. Rarely, fluid replacement may be required.

Cramping is also common, especially at the end of the dialysis session after large amounts of fluid and electrolytes have been removed. Severe cramping may require administration of normal saline. For patients who are significantly bothered by cramping, hydromorphone (Dilaudid) 1–2 mg orally may be given one hour before the usual onset of cramping. Hydromorphone has the advantage of not being dialyzed out of the patient's system.

The indication for transplantation is ESRD, or a GFR of <15 mL/min/1.73 m² [9]. In recent years, the process for selection of kidney transplant has liberalized, with larger numbers of elderly patients being accepted for transplantation. In 1991, 30% of kidney transplant recipients were older than 50 years of age. In 2021, the rate of kidney transplantation is 42.3 per 100 person-years among individuals 0 to 17 years of age, 9.8 among individuals 18 to 44 years of age, 5.0 among individuals 45 to 64 years of age, 2.9 among individuals 65 to 74 years of age, and 0.5 among individuals 75 years of age or older. This distribution represented a slightly younger mix of transplant recipients compared to 2017 [11]. Guidelines for selection of patients for transplantation vary from program to program. Generally, metastatic disease or severe pulmonary or heart disease are exclusionary factors. Human immunodeficiency virus (HIV) is no longer considered an absolute contraindication, and studies have shown that patients with ESRD and HIV nephropathy have an increased life expectancy when treated with transplantation versus dialysis [109].

Allocation of all transplants in the United States is managed by the United Network for Organ Sharing (UNOS). Kidney transplant guidelines place the highest considerations on histocompatibility and time spent on the transplant list [110]. Children suffering from ESRD will lose growth (and possibly other milestones) while on dialysis, so they are given priority. The median adult wait time for a cadaver kidney is just over four years [108].

One result of this method of allocation is a potential mismatch of grafts and patients. If a patient with a life expectancy of 10 to 20 years receives a kidney from a donor who is/was 20 years of age (with a potential for 50 to 60 years of function), the transplanted kidney will potentially be underutilized. Worse, if a patient with a 40- to 50-year life expectancy receives a kidney from an older donor, he or she will likely outlive the donated kidney. In fact, approximately 14% of all patients awaiting transplantation have already received at least one transplant [11].

To address these problems and others, in 2021, the Organ Procurement and Transplantation Network (OPTN) (which operates under contract with the U.S. Department of Health and Human Services by UNOS) released a new policy for matching kidney transplant candidates with organs from deceased donors [111]. The new policy is "projected to increase equity in transplant access for candidates nationwide" by replacing "distribution based on donation service area and OPTN region with a more consistent measure of distance between the donor hospital and the transplant hospital for each candidate" [111]. Additional policy updates implemented at the same time involve allocation of kidneys from Alaska, prioritization of medically urgent patients, and how released kidneys are distributed in the new system when the original intended candidate is not able to be transplanted [111]. The OPTN projects that the new policies will improve transplant access for key groups of candidates, including children, women, ethnic minorities, and candidates who are particularly hard to match for biological reasons [111].

Transplanted kidneys are generally placed in the extraperitoneal space in the right iliac fossa. Pediatric patients can have their grafts placed in the intraperitoneal space. The major consideration for placement of the graft is surgical access to the renal arteries, renal veins, and the ureter. Failed kidneys are rarely removed unless infection or carcinoma is present. The donor's renal artery is usually anastomosed to the recipient internal iliac artery, and the donor renal vein is connected to the recipient external iliac vein. Lastly, the donor ureter is attached to the recipient bladder.

Prior to the advent of highly active antiretroviral therapy (HAART), the incidence of AKI in HIV-positive individuals was fairly high, affecting up to 20% of hospitalized patients [131]. After the introduction of HAART, the incidence of AKI in hospitalized patients has fallen to approximately 3%, which is still about twice that of non-HIV-positive hospitalized individuals [131,132]. The causes of AKI in hospitalized patients are quite heterogeneous, including hypovolemia, acute tubular necrosis, hemolytic uremic syndrome, and drug-induced AKI and HIV-associated nephropathy [131].

The incidence of CKD among patients with HIV infection varies widely based on the population sampled and on the definition of CKD used [132]. Furthermore, some studies have used the presence of proteinuria as a marker of disease (due to the ease of measurement) rather than NKF guidelines [132]. Epidemiologic studies place the rate of kidney disease in HIV-infected populations in the United States at approximately 7% to 8%, with microalbuminuria present in as many as approximately 30% of patients [131].

In other areas of the world, CKD in HIV-infected patients is not well documented and the rate varies based on definitions and methods of sampling. For instance, screening studies defining persistent proteinuria as an indicator of CKD revealed prevalence rates of 27% in India, 12.3% in Iran, and 5.6% in Brazil [132]. In Africa, the prevalence of HIV-associated renal disease is widely variable at 38% in Nigeria, 33.5% in Zambia, 20% in Uganda, and 5.5% to 6% in South Africa [132]. Rates are always found to be higher than those in noninfected populations [131].

The prevalence of asymptomatic HIV-associated nephropathy may be much higher than statistics suggest, as HIV-associated nephropathy is only diagnosed by kidney biopsy [131]. Individuals with HIV comprise an estimated 1.5% of the United States ESRD population, and the prevalence of ESRD in this population continues to rise [132]. It has also been found to disproportionately affect minority patients. A study of 2 million U.S. veterans found that HIV conferred the same risk of ESRD among black patients as diabetes, but no such increased risk of ESRD was found among white patients with HIV [133]. HIV-associated nephropathy as a cause of ESRD affects almost exclusively persons of African descent, who account for approximately 90% of cases [132].

Treatment

The Infectious Diseases Society of America recommends that HIV-infected patients with kidney disease be referred to a nephrologist for diagnostic evaluation when there is a clinically significant decline in GFR that fails to resolve after potential nephrotoxic drugs are removed, there is albuminuria in excess of 300 mg per day, hematuria is combined with either albuminuria/proteinuria or increasing blood pressure, or for advanced CKD management.

(https://academic.oup.com/cid/article/59/9/e96/422813 Last Accessed: November 21, 2024)

Strength of Recommendation/Level of Evidence: Strong/low

The primary goal of treatment of HIV-associated nephropathy is to prevent or limit the progression of the HIV infection. A diagnosis of HIV-associated nephropathy is an indication for the use of HAART, regardless of viral load [134]. Because proteinuria is present in HIV-associated nephropathy, the use of ACE inhibitors may be beneficial, and their use has been shown to decrease the incidence of ESRD in patients with HIV-associated nephropathy [131,132,135].

In general, the treatment of renal disease and ESRD in HIV-infected populations should follow the same standards as those noninfected patients with renal disease. The same standards of care for anemia, dialysis, transplantation, and prevention of CAD should be followed. Of particular importance is following guidelines for dosage adjustment of medications [132]. Most HIV drugs require adjustment in renal failure, and clinicians should follow manufacturers' recommendations.

Hemodialysis

While the presence of HIV infection calls for rigorous adherence of Universal Precautions, special techniques are not required for hemodialysis. In fact, Standard Precautions are used for all patients on hemodialysis regardless of infection status. The dialysate should be regarded as potentially infectious body fluid, although no transmissions have been linked to dialysate to date [136]. Because of the increased susceptibility to infections, peritoneal dialysis is not widely advocated for this patient population [132].

Kidney Transplantation

With the widespread use of HAART, studies have shown that patients with HIV do well after transplantation [134]. Concerns that immunosuppression would accelerate the progression of HIV disease have not been supported. HIV-positive individuals with stable disease pretransplant and no prior opportunistic infections have been found to continue to have stable disease post-transplant [132]. However, patients with HIV experience high rates of acute allograft rejection [132]. Guidelines generally call for adult transplant candidates to have a CD4 count greater than 300 cells/mm³ and an undetectable viral load [109,132]. Guidelines vary by center and differ for children, who generally should be transplanted as soon as possible to avoid developmental delays [131].

It is important for clinicians not to regard HIV disease as a terminal illness. The advent of HAART has transformed HIV into a chronic disease, and patients with HIV may live for decades with appropriate treatment [137]. Like many chronic illnesses, renal function may be affected and should be managed in accordance with established guidelines.

In even a typical, uncomplicated pregnancy, renal dynamics are affected. Renal plasma flow increases dramatically, and by the second trimester, GFRs can reach 150% of normal [147,148]. Accordingly, BUN and serum creatinine normally decrease. Blood pressure should fall in the first 24 weeks by approximately 10 mm Hg and return to normal levels by term [147]. Glucosuria also occurs in normal pregnancy due to changes in tubular function and decreased serum sodium levels (by approximately 5 mEq/L). Overall kidney size increases by approximately 1–1.5 cm, and the ureters dilate. This, coupled with changes in the pelvis, can lead to urinary stasis and an increase in urinary tract infections. Proteinuria up to 300 mg/day may occur even in normal pregnancy [147,148].

Renal disease associated with pregnancy can take many forms. Perhaps the most common is prerenal azotemia associated with hyperemesis gravidarum. Treatment of this condition usually only requires replacement of fluids via intravenous administration. Acute tubular necrosis can occur with severe dehydration as well as secondary to shock or sepsis (or septic abortion). Treatment can require fluids, antibiotics, and if severe, dialysis [147].

Pre-eclampsia is a syndrome of proteinuria and hypertension that affects up to 5% of all pregnancies, while eclampsia is the occurrence of seizures in a patient with pre-eclampsia [147]. Pre-eclampsia does not usually develop until after the 32nd week of pregnancy, but it may develop much earlier in patients with CKD or hypertension. Risks factors include prepregnancy hypertension, diabetes, and CKD. Management of pre-eclampsia begins with bed rest but can include use of antihypertensives. Methyldopa, labetalol, and hydralazine are generally used, although this indication is off label. ACE inhibitors are contraindicated in pregnancy and can cause fetal loss, and diuretics are usually avoided in euvolemic patients. Intravenous magnesium sulfate can be used to prevent seizures. After 32 weeks' gestation, worsening pre-eclampsia warrants early delivery; eclampsia always mandates immediate delivery [147,148].

In pregnant women, CKD can affect both the outcome of the pregnancy and the long-term outcome of the underlying renal disease. While fertility is decreased in CKD, pregnancy can occur, even in patients on dialysis. Outcomes vary considerably with degree of disease. Women with stable systemic lupus erythematosus (SLE), asymptomatic autosomal dominant polycystic kidney disease, or mild CKD and no hypertension may expect to have fairly normal outcomes [147].

Effects of pregnancy on CKD include deterioration of renal function. If this occurs quickly in early pregnancy, with no apparent diagnosis, renal biopsy should be considered [147]. In patients with mild CKD, renal function may be entirely preserved. Studies have shown that only 16% of pregnant patients with mild CKD and a baseline serum creatinine less than 1.5 mg/dL experienced a decline in renal function and only 6% of this subgroup progressed postpartum to ESRD [149]. Of patients with moderate CKD (serum creatinine: 1.5–2.4 mg/dL), one study found that 20% developed ESRD [150]. So, outcomes vary widely but are fairly predictable based on prepregnancy level of renal function [147].

SLE is frequently seen in women of childbearing age and is a common cause of renal disease in pregnancy. Approximately half of all SLE patients will experience a flare of their disease while pregnant, and in some cases, this manifests as lupus nephritis [147]. Lupus nephritis is characterized by proteinuria, hypertension, and decreased GFR. This constellation of symptoms may make lupus nephritis difficult to differentiate from pre-eclampsia, but a biochemical work-up for markers of lupus is helpful in making the distinction. Treatment of SLE flares in pregnancy is difficult due to the teratogenic nature of most SLE drugs, and up to 50% of all of these pregnancies result in fetal loss [147,148].

While ESRD results in decreased fertility, 1% to 7% of all women on dialysis who are of childbearing age will become pregnant [151]. Successful pregnancies have been documented, especially since 1980, but outcomes are still grim; only 25% to 50% of pregnancies result in live births [151]. Many pregnancies result in spontaneous abortion in the second trimester, and 85% of surviving infants are born premature. Outcomes for pregnancies that continue are good, with a fetal survival rate as high as 71% [147]. Maternal complications include severe worsening of hypertension and even death. It should be noted that the diagnosis of pregnancy cannot be made based on the usual measure of human chorionic gonadotropin (hCG), as beta-hCG is elevated in patients on dialysis [147,148]. Ultrasound is generally necessary for confirmation of suspected pregnancy.

Since 1958, more than 5,000 women have given birth post-transplant [152]. Women who previously were unable to conceive while undergoing dialysis often have a return of fertility after transplant, and up to 12% of all women of childbearing age may become pregnant [151]. Outcomes are generally quite good, with up to a 90% fetal survival rate [148]. Patients should be counseled that a properly planned and monitored pregnancy is possible, including preconception counseling by the transplant team. Recommendations for patients considering pregnancy include changing immunosuppressive regimens to limit dosages of prednisone and azathioprine and stopping mycophenolate mofetil and sirolimus six weeks prior to conception. Ideally, the patient should be two years post-transplant and in good health, with a serum creatinine level less than 2.0 mg/dL. There should be no recent or ongoing rejection, and patients should be normotensive and have minimal or no proteinuria [147,148].

Even patients with optimal prepregnancy planning and good health can expect to experience some complications. The need to take immunosuppressive agents raises the maternal risk for hypertension and the fetal risk for size smaller than gestational age. Pre-eclampsia occurs in one-third of all transplant patients, and 50% of pregnancies require preterm delivery secondary to hypertension. Finally, there is an increased risk of opportunistic infections such as cytomegalovirus, herpes, and toxoplasmosis [147].

It is crucial for healthcare professionals to realize that chronic illness is often a new and unanticipated event to the patient and family. Therefore, concrete information is vital. At the initial diagnosis, the family may be overwhelmed and struggling to come to terms with the illness. They may also be grappling to understand new medical jargon and trying to assimilate a tremendous amount of information in order to make decisions about medical care plans. At this juncture, enhancing communication between the primary physician or nephrology team and the patient/family is the primary goal [155]. Technical information about the illness, prognosis, and care regimen should be conveyed. Healthcare professionals should be sensitive to the fact that this information may need to be relayed on several occasions. During this time, a list of resources and referrals may be helpful [155].

It is beneficial for caregivers and family members to understand normal changes that are part of human development and the life cycle, changes that are specifically related to the illness, or possibly an interaction of both [156]. Social isolation may occur. Therefore, it becomes a complicated issue to determine whether a particular behavioral change is the result of normal human development or illness-related.

Technical information related to the daily care of the patient should also be relayed. Family members may have to be taught how to lift and move patients without hurting themselves or the patient and how to administer medications or dialysis [156]. Family members should be reminded and educated about the physical consequences of the illness. Patients, for example, may experience fatigue as a result of the medications and/or the illness; however, some family members may become frustrated with the patient and interpret the patient as being lazy and taking advantage of the sick role [156]. Healthcare professionals should be fully knowledgeable about resources on both the local and national level to assist families in coordinating care for both the patient and themselves. Resources and services include places to access special equipment, legal and financial information, respite care, counseling, and support groups [156].

The emphasis is to provide an opportunity for patients and family members to explore their feelings of loss, sorrow, mourning, and grief. Interventions also focus on helping to cope with or accept loss of physical functioning and capabilities [157].

Chronic illness can be the source of ambiguous loss, which is defined as loss without the finality of death but also with no certainty that the person will return to his or her previous level of functioning [158]. The goal is not necessarily to eliminate this sense of loss, but rather to increase family tolerance and coping. After identifying the loss, the family would work collaboratively to make decisions regarding day-to-day care and activities. Depression, which is commonly experienced among caregivers, may also be viewed as symptomatic of ambiguous loss. Therefore, practitioners can help encourage caregivers to not assume all the burden of responsibility, but rather to delegate and distribute the work. This may mean obtaining respite assistance [158].

One of the more difficult tasks is for patients and family members to understand and make sense of the ambiguous loss [158]. They can begin by looking at their own family's socialization, spiritual and religious values, and perspective (e.g., viewing the world optimistically).

In order to prevent burnout, family members and caregivers should learn to take care of themselves. Caregivers often experience a host of conflicting emotions, including guilt, sadness, anxiety, and exhaustion. They often feel that they should not express negative feelings, believing that it will adversely affect the patient [156]. Healthcare professionals should routinely ask caregivers how they are feeling and coping, and then validate their experiences and feelings.

Caregivers should also be encouraged to obtain respite care. Respite refers to any type of service, either informal or formal, that offers relief and assistance for family members to cope with the challenges of chronic illness [159]. Informal respite assistance may include extended family members, neighbors, and friends who might periodically help with meal preparations, transportation, or housekeeping.

Family therapy can be a useful intervention to assist families in acknowledging and accepting the patient's illness as well as the treatment plan and prognosis [155]. It can help families develop coping skills to manage the challenges of the continual stressors related to chronic illness and identify maladaptive family patterns, such as enmeshment, triangulation, overprotectiveness, and rigidity [155]. In addition, role expectations can be clarified among family members, and lines of communication can be opened, and at times, restored, if certain family members feel overloaded with caregiving responsibilities [156].

Psychoeducational groups were first used in families with members who had schizophrenia; however, they have been adapted for use with other clinical populations. Psychoeducational groups typically involve a didactic and support component, whereby family members convene for 10 to 12 structured sessions on a biweekly basis [160]. The didactic component focuses on both cognitive information and behavioral change. Caregivers, for example, listen to a series of mini-lectures that focus on disease etiology, treatment, and management [160]. Problem-solving skills and coping strategies are often discussed. Caregivers are encouraged to use these newly-learned skills and apply them at home. The support component of the psychoeducational groups provides a forum for family members to talk about various issues that may come up in the caregiving situation. Facilitators and other family members provide validation and recognition of feelings.

Support and self-help groups are facilitated either by volunteers or healthcare professionals. They may vary, but will provide information regarding the illness and disease process, symptom management, emotional support around caregiving, advocacy, or a combination of these services [156]. Several support groups exist for patients, and more information about specific online or in-person groups is available from the American Association of Kidney Patients, the Renal Support Network, and the Kidney and Urology Foundation of America (Resources).

Provisions for patients with limited English language proficiency are required under federal law, and the Department of Health and Human Services and the Office of Civil Rights view a lack of adequate interpretation as discrimination, based on the Civil Rights Act of 1964 [161]. Additionally, adhering to guidelines for working with patients with limited English proficiency helps to foster a beneficial working relationship and improved patient outcomes.

According to U.S. Census Bureau data from 2022, more than 67.8 million Americans speak a language other than English in the home, with more than 25.7 million of them (8.2% of the population) reporting that they speak English less than "very well" [162]. Clinicians should ask their patients what language is spoken at home and what language they prefer for their medical care information, as some patients prefer their native language even though they have said they can understand and discuss medical information in English [163].

When the healthcare professional and the patient speak different languages, a professional interpreter should be used. Studies have demonstrated that the use of professional interpreters rather than "ad hoc" interpreters (untrained staff members, family members, friends) facilitates a broader understanding and leads to better outcomes [161,164,165]. Using a family member as a translator confuses the role of that member in the family, may involve confidentiality issues, and may lead to a modified message to protect the patient. In addition, individuals with limited English language skills have indicated a preference for professional interpreters rather than family members [166]. Professional interpreters have recommended that clinicians can further enhance the quality of care by meeting with interpreters before discussions of bad news and by explicitly discussing with the interpreter whether strict interpretation or cultural brokering is expected [167].

The practitioner should always address the patient directly. For example, the practitioner should query the patient, "How do you feel?" versus asking the interpreter, "How does she feel?" The practitioner should also always refer to the patient as "Mr./Mrs. D," rather than "he" or "she." This avoids objectifying the patient. In addition, at the start of the session, the practitioner should clearly identify his/her role and the interpreter's role [168]. This will prevent the patient from developing a primary relationship or alliance with the interpreter, turning to the interpreter as the one who sets the intervention [169]. The practitioner also should be attuned to the age, gender, class, and/or ethnic differences between the patient and the interpreter [168]. For example, if the patient is an older Asian male immigrant, and the interpreter is a young, Asian female, the practitioner must be sensitive to whether the patient is uncomfortable, given the fact he may be more accustomed to patriarchal authority structures. At the conclusion of the session, it is advisable to have a debriefing time between the practitioner and the interpreter to review the session [168,169,170].

On the patients' side, they may be wary about utilizing interpreters for a host of reasons. They may find it difficult to express themselves through an interpreter [168]. If an interpreter is from the same community as the patient, the patient may have concerns about sharing private information with an individual who is known in the community and the extent to which the information disclosed would remain confidential. In some cases, raising the issue of obtaining an interpreter causes the patient to feel insulted that their language proficiency has been questioned. Finally, if an interpreter is from a conflicting ethnic group, the patient may refuse having interpreter services. The ideal situation is to have a well-trained interpreter who is familiar with health and mental health concepts.

Immigrant patients with renal failure may feel unable to return to their home countries, due to a lack of available dialysis and proper specialty care in their home countries. Changes in healthcare law restricting federal funding to legal residents may cause significant problems for hospital-based dialysis centers providing lifesaving care for patients who have no means of reimbursement and no medical services waiting for them in their home countries.

An end-of-life discussion is recommended in the presence of stage 4 or 5 CKD or ESRD [171,172,173]. Hospice is generally approved when patients with ESRD are not candidates for dialysis, have a creatinine clearance less than 15 mL/minute, and/or have a serum creatinine level greater than 8 mg/dL (or 6 mg/dL in patients with diabetes) [174]. Guidelines from the Renal Physicians Association note that prognosis should be fully discussed with all patients who have stage 4 or 5 disease or ESRD [172]. Clinicians should carefully prepare for the discussion of prognosis by reviewing the patient's medical record and talking to other healthcare professionals involved in the care of the patient [175]. Because there is variation among patients with regard to their desire for information, clinicians should follow the "ask-tell-ask" approach: ask the patient if he or she is willing to discuss prognosis; if yes, discuss the prognosis and then ask the patient to confirm his or her understanding [171,176]. When discussing prognosis, quantitative estimates are more understandable for patients and family than qualitative ones (e.g., "poor"), and general timeframes for survival should be given [171,176,177,178]. In addition, clinicians should emphasize that prognosis is determined by looking at large groups of patients and that it is harder to predict survival for an individual [171,172]. The discussion of prognosis is often not documented in the patient's record, but it should be [175].

Clinical guidelines have begun to address the use of aggressive treatment at the end of life. The Renal Physicians Association recommends forgoing dialysis for patients with CKD or ESRD who have "very poor prognosis" [172]. Early discussion of preferences for life-sustaining measures is especially important. Nearly three-quarters of people will be unable to participate in some or all of the decisions about their care at the end of life [179]. Documentation of preferences helps inform decision making by the physician and the patient's healthcare proxy (surrogate decision maker). Clinicians should encourage their patients to designate a healthcare proxy early in the course of a life-limiting disease [171,180,181]. Patients should be urged to clarify their wishes with their chosen proxy, as a proxy often inaccurately predicts a patient's wishes or may have values that conflict with those of the patient [179].

Patient A is a white man, 55 years of age, with diabetes. His HbA1c is 11%, and he suffers from diabetic retinopathy. Upon presentation, his blood pressure is 147/88 mm Hg, cholesterol is 213 mg/dL, and LDL is 136 mg/dL. His serum creatinine is 1.3 mg/dL. He is 5 foot 10 inches tall, his weight is 223 pounds, and he suffers from peripheral neuropathy. Patient A reports not having seen a primary care provider in years and is not on medication. He works at a factory and does not have health insurance.

Discussion : A few points come to mind when reviewing Patient A's history. Patients with poorly controlled diabetes are at an increased risk of renal disease. For every point the HbA1c is above normal, the incidence of end organ damage rises 10%. In this patient, the presence of end organ damage (i.e., retinopathy and neuropathy) indicates a high probability of renal disease. It is important to remember serum creatinine does not rise substantially until late in the renal disease process.

Patient A is found to have proteinuria on dipstick testing. A 24-hour urine collection reveals a GFR of 57 mL/min/1.73 m². This categorizes the patient as having stage 3 CKD with hypertension and diabetes.

Patient A's primary care physician discusses this diagnosis with him and they develop a management plan, including medication and diet to better control his diabetes, with an HbA1c goal of less than 7%. He is also placed on an ACE inhibitor and a statin to achieve a blood pressure less than 130/85 mm Hg and an LDL less than 70 mg/dL. Because the patient has no health insurance, generic formulations of simvastatin (for hyperlipidemia) and lisinopril (for hypertension) are prescribed. The patient also starts generic metformin 1 g twice daily.

Discussion : According to the NKF guideline, the goals of treatment should be to diagnose and treat the specific causes of CKD, reduce the risks of cardiovascular disease, slow progression, and evaluate and treat complications and comorbidities.

When given to patients with advanced renal disease, metformin can lead to lactic acidosis, which can be fatal. Therefore, it should not be prescribed to men with serum creatinine levels of 1.5 mg/dL or greater or to women with serum creatinine levels of 1.4 mg/dL or greater. Patient A's serum creatinine will be regularly monitored; if the level rises to greater than 1.5 mg/dL, the metformin must be halted due to the risk of lactic acidosis.

Goals for HbA1c, LDL, and blood pressure should be secondary prevention goals for patients with diabetes and CKD. The target LDL is <70 mg/dL, and blood pressure should be less than 130/85 mm Hg. The HbA1c goal for patients with diabetes should be within 10% of normal, taking into account that studies have shown that older patients with cardiovascular disease actually have worse outcomes with HbA1c levels less than 6%.

Use of less expensive generic medications can greatly increase compliance, especially for uninsured patients. So, this was a good choice for Patient A. The costs associated with tests should also be considered. Although Medicare prefers reimbursing for "bundled" labs (e.g., chem-7 or chem-20), very often a single test, such as a serum creatinine, may be less expensive than a bundled panel of tests. The HbA1c is a test that changes slowly over the course of 90 days (the average lifespan of a red blood cell) and does not require more frequent monitoring. After the LDL goal has been reached, monitoring cholesterol less frequently may be considered as well.

Patient B is a white woman, 35 years of age, with a history of frequent urinary tract infections who now presents with gross hematuria. On physical exam, she is thin with a palpably enlarged right kidney. On questioning, she states that her mother had some sort of "cyst disease" of the kidney. She further states that her mother died of a heart attack several years ago, at 62 years of age. A renal ultrasound reveals numerous large, fluid-filled cysts on the right kidney and several cysts on the left kidney. Further imaging also reveals a fluid-filled cyst visible on the liver. A consultation with nephrology and a geneticist results in a diagnosis of autosomal dominant polycystic kidney disease (ADPKD).

Discussion : ADPKD is the fourth leading cause and the leading genetic cause of ESRD, and the most common life-threatening hereditary disease in the United States. ADPKD occurs in approximately one of every 1,000 live births. Children of affected individuals have a 50% chance of inheriting the disorder.

Patients with ADPKD can present with flank pain, hematuria, and/or palpable kidneys. Individuals with a family history are considered to have ADPKD if ultrasound reveals two unilateral or bilateral cysts in patients 15 to 30 years of age, two or more cysts in each kidney for patients 30 to 59 years of age, or four or more cysts in each kidney in patients older than 60 years of age. For patients with no known genetic risks (either from family history or genetic testing), the diagnostic criteria are three or more unilateral or bilateral cysts in patients 15 to 39 years of age or two or more cysts in each kidney for patients 30 to 59 years of age.

While the predominant clinical feature of ADPKD is renal disease (50% of affected patients have ESRD by 60 years of age), extrarenal manifestations are also common, which suggests that the disease may involve a generalized collagen disorder. As well as liver and pancreatic cysts, patients have an increased risk of cerebral hemorrhage due to intracranial aneurysms, cardiac valve abnormalities, aortic root dilation, and abdominal hernias.

Patient C is a black woman, 53 years of age, who is currently employed as an administrative assistant at a Veterans' Hospital. She has a long history of bipolar disorder and has been stable for many years on a combination of lithium and olanzapine. She states that in the last several years her weight has increased from 155 pounds to 217 pounds; her height is 5 feet 4 inches. She complains of frequent thirst and urination, lethargy, weakness, and blurred vision. A medical work-up reveals the following:

Discussion : Many widely prescribed medications for bipolar disorder have a variety of serious long-term side effects. Olanzapine has a documented risk of weight gain, hyperglycemia, type 2 diabetes, and in rare cases, diabetic ketoacidosis. The FDA requires a "black box" warning in the medication packaging warning of these side effects. While widely used for many years, lithium also has both endocrine and renal side effects.

Patient C is directed to report to her local emergency room, where she receives intravenous fluids for dehydration, insulin, amlodipine for hypertension, and glyburide for diabetes. Her primary care practitioner starts her on levothyroxine for hypothyroidism and simvastatin for high cholesterol. She is also referred to endocrinology and nephrology. Her psychiatrist will conduct an evaluation of her psychiatric medications.

Discussion : Collaboration between specialists and primary care providers is a necessary component to care of patients with renal disease. Many psychiatric medications can impact the care of patients with renal disease, worsen pre-existing diabetes and hypertension, or cause weight gain. Often, these side effects may be lessened by a change in medications. While psychiatric providers may be reluctant to change medications when a patient has been stabilized on his or her current regimen, patient safety may necessitate it. It is important that all team members be alert for signs and symptoms of psychiatric decompensation, especially if a patient is undergoing medication changes while simultaneously dealing with a new medical diagnosis.