Kidney diseases

Kidney diseases

Team Medics for Humanity

 

Introduction

The kidneys are a crucial part of the renal system, regulating plasma osmolarity by modulation of the amounts of water, solutes, and electrolytes in the blood. The kidneys ensure long term acid-base balance, produce erythropoietin to stimulate the production of red blood cells, secrete renin for blood pressure regulation, and convert vitamin D to its active form, among other relevant fuctions (1).

Kidney pathologies have a wide range of clinical presentations and ethiologies including many conditions, diseases or medicines. As a very general classification, kidney problems can be divided in acute, those that can develop suddenly, or chronic, those that develop over the long term. Acute kidney injure (AKI) is more commonly reversible than chronic kidney disease (CDK) (1). Recent efforts aimed to establish standardized definitions and classification systems for AKI and CKD, although there are some abnormalities of kidney function and structure that do not meet the current criteria for either disorder (2). The current definitions of AKI and CKD are based on graded relationships between acute changes or sustained reductions, respectively, in laboratory measures of kidney function with important clinical outcomes (2). In addition to laboratory parameters, other techniques such as ultrasounds can help to determine whether kidney problems are acute or chronic. Normal-sized kidneys can be present in either condition but, when both kidneys are smaller than normal, CKD is usually expectable (3).

 

The burden of kidney diseases

Kidney diseases have an indirect impact on global morbidity and mortality by increasing the risks associated with at least five other major killers: cardiovascular diseases, diabetes, hypertension, infection with human immunodeficiency virus (HIV), and malaria (4).

Deaths caused by kidney failure have seen a rising trend in the last years, with a 32% increase from 2005 to 2015, reaching 1.2 million in the last estimates (4). Between 2.3 and 7.1 million people with end-stage kidney disease – the last stage of CKD with kidneys functioning at only 10-15% of their normal capacity- died without access to chronic dialysis in 2010 (5). Moreover, around 1.7 million people die each year because of AKI. Overall, the estimations calculate between 5-10 million deaths per year due to kidney diseases (4). The true burden of kidney diseases is probably underestimated, since reliable epidemiological data are lacking in part due to poor access to healthcare and diagnostic services in many parts of the world, as well as a lack of awareness. It has been predicted that at least as many deaths are attributable to kidney disease as to cancer, diabetes or respiratory diseases yearly. The estimated number of disability-adjusted life-years (DALYs) attributable to kidney disease globally increased from 19 million in 1990 to 33 million in 2013 (4).

Kidney diseases are associated with a tremendous economic burden, with high-income countries spending 2–3% of the annual healthcare budget on the treatment of end-stage kidney disease for a proportion of 0.03% of the total population (4). Over 2.62 million people received dialysis worldwide in 2010, with a projected increase up to a double amount by 2030. Milder forms of CKD, on the other hand, may requiere higher expenditure than the total cost of treating end-stage kidney disease. In 2015 only in the USA, Medicare national health insurance allocated around US$100 billion to CKD, more than one third for the treatment of end-stage kidney disease (6). Much of the morbidity, mortality and health expenditure previously attributed to diabetes and hypertension has been identified to be due to kidney diseases and its complications (4).

Acute kidney injury (AKI)

AKI is a heterogeneous group of conditions characterized by an abrupt reduction in glomerular filtration rate (GFR), manifested by a reversible increase in nitrogen waste products -measured by blood urea nitrogen and serum creatinine concentration- or oliguria, and that can be classified by stage and cause (7). AKI is usually caused by an event that leads to kidney malfunction, such as dehydration, blood loss from major surgery or injury, or the use of medicines (3).

Most cases of AKI occur in people who are already in the hospital for other reasons (it affects approximately 20% of hospitalized patients) (3,7). In these patients, AKI is usually identified when routine tests detect a sudden increase in creatinine and blood urea nitrogen levels in blood, pointing to a decrease of kidney function. Symptoms of reduced kidney function, such as fluid retention or electrolyte imbalance, are more likely to develop with AKI, regardless of how long the kidney has been malfunctioning, than with CKD (3).

AKI is associated with major complications including volume overload, electrolyte disorders, uremic complications, and drug toxicity. Although several classification systems have been developed for AKI, they still present some shortcomings. In particular, the use of serum creatinine levels to determine the stage, instead of a primary etiologic or anatomic diagnosis, may provide an inadequate quantitative assessment of excretory dysfunction, and complicate the distinction of different etiologies and the subsequent application of personalized therapies (8). The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline proposed as a functional criteria for AKI an increase in serum creatinin by 50% within seven days, or an increase in serum creatinin by 0.3 mg/dL (26.5 μmol/L) within two days, or oliguria (2).

Management of AKI relies on specific treatment depending on the etiology, which makes paramount to determine the causes in order to implement the therapy, together with supportive treatment to prevent or manage complications (7). Kidney replacement therapy may be required when complications cannot be managed with medical therapy alone, approximately in 5-6% of critically ill patients (7). Early initiation of dialysis (i.e., within 8 hours of stage 2 AKI) may improve outcomes, although there is no superior form of renal replacement therapy for AKI and increased dose of dialysis does not appear to confer any benefit (9). The mortality rate in patients requiring kidney replacement therapy remains approximately 50% (7). Importantly, patients suffering an episode of AKI should be evaluated for resolution of injury with follow-up within the first 90 days to evaluate potential development of CKD (9).

Risk factors for AKI include age, comorbid diseases, proteinuria, nephrotoxic exposures, major surgery -in particular cardiac surgery-, sepsis, fluid resuscitation, and volume status. Comorbidities including CKD, diabetes, hypertension, coronary artery disease, heart failure, liver disease, and chronic obstructive pulmonary disease are also risk factors for AKI (9). Hospitalized patients, especially critically ill patients, also present a higher risk of AKI, since they are often exposed to several nephrotoxins and contrast agents, and commonly receive medications such as antimicrobials, nonsteroidal anti-inflammatory drugs (NSAIDs), and proton pump inhibitors. Finally, the choice of fluid for resuscitation may also be a risk factor because hydroxyethyl starch has been associated with increased risk of AKI compared with crystalloids (9).

The causes of AKI can be classified into three broad groups:

  • pre-renal or hemodynamic, due to hypoperfusion to the kidney
  • intrinsic, meaning a structural damage to the kidney
  • post-renal, because the urinary outflow is obstructed

Pre-renal causes of AKI

Pre-renal AKI is the most frequent kidney injury, due to a decreased renal perfusion of the kidney with or without systemic arterial hypotension (9). Among the main causes, we can mention dehydratation (due to inadequate fluid intake, vomiting, diarrhea, or fever), massive hemorrhage caused by a trauma which decreases circulating volume, heart failure, cirrhosis and sepsis. In particular, sepsis and septic shock are the most common causes of AKI in the intensive care unit, probably due to an inflammatory response to infection leading to hypoperfusion and multi-organ failure (9). The second most common causes of AKI are cardiac surgery and heart failure. Finally, hepatorenal syndrome, burns, and trauma can also cause hypoperfusion of the kidneys (9).

Regarding medications that may lead to AKI, we can highlight angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), calcineurin inhibitors, cyclooxygenase-2 inhibitors, diuretics, and NSAIDs (9).

Intrinsic causes of AKI

A wide range of etiologies, disease conditions, or offending drugs can damage the glomerulus, tubules, interstitium, and vasculature, causing AKI. The immune system plays a key role in these cases. Drugs acting as direct nephrotoxins or stimulating the immune response can cause the intrinsic injury.

Glomerular injury may occur from autoimmune disorders or other immune-mediated diseases or conditions such as lupus nephritis, immunoglobulin A nephropathy, Wegner syndrome, polyarteritis nodosa, or post-streptococcal infection (9). Anti-cancer drugs, including interferon, pamidronate, gemcitabine, and vascular endothelial growth factor inhibitors, are the most frequent agents leading to glomerular injury, in particular the new immune-targeted therapies (9).

Tubular injury frequently occurs due to the administration of antimicrobials and nephrotoxic drugs (aminoglycosides, amphotericin B, carboplatin, cisplatin, cyclophosphamide, ifosfamide, pentamidine, radiocontrast media, vancomycin, etc.). For example, conventional amphotericin B can cause AKI in around 28% of cases, while contrast-induced nephrotoxicity occurs in up to 30% of patients (9). Being the organ in charge of eliminating medications, the kidney is vulnerable to the adverse effects of medications.

Acute interstitial nephritis may be caused by infections (pyelonephritis, renal tuberculosis or fungal nephritis), medications (antibiotics, NSAIDs, and diuretics), or immune disorders. The list of drugs associated with acute interstitial nephritis is long and includes allopurinol; azathioprine; Chinese herbs such as Stephania tetrandra, Magnolia officinalis, and Aristolochia fangchi; cimetidine; diuretics such as thiazides and furosemide; NSAIDs; phenytoin; proton pump inhibitors; quinolones; rifampin; semisynthetic penicillins such as ampicillin, nafcillin, and oxacillin; sulfonamides; and vancomycin (9).

There are several renal vascular disorders that can cause AKI, such as vasculitis, malignant hypertension, scleroderma, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, thrombotic microangiopathies (which can be caused by some chemotherapeutic agents), disseminated intravascular coagulation, mechanical renal artery occlusion (surgery, emboli, thrombotic occlusion), and renal venous thrombosis (9).

Post-renal causes of AKI

Kidney obstruction can cause the so-called post-renal AKI. Among the etiologies, nephrolithiasis, benign prostatic hypertrophy, and surgical causes have been previously identified. Renal calculi due to calcium, uric acid, struvite, and cysteine accumulation may also lead to kidney obstruction, as well as some drugs that can crystallize due to their low solubility in urine (9).

Epidemiology of AKI

A few years ago, the International Society of Nephrology (ISN) launched the 0by25 initiative which aims to eliminate preventable deaths from AKI worldwide by 2025 (10). According to their evidences about the global burden of AKI, every year around 13.3 million cases of AKI occur worldwide. Of them, the estimated incidence in emerging countries is 11.3 million. AKI causes 1.7 million deaths per year globally, of which 1.4 million occur in low- and middle-income countries (10).

AKI poses a heavy challenge in Africa because of the high disease burden -in particular, AKI related to HIV, malaria, nephrotoxins, or diarrheal diseases-, the late presentation of patients to healthcare facilities, and the lack of resources for adequate management of the condition (11). Although there are not comprehensive statistics, all these factors contribute to a completely different AKI epidemiologic pattern in African countries than in more developed ones. The main causes of AKI in Africa include infections (malaria, HIV, diarrheal diseases and others), nephrotoxins, obstetric and surgical complications, and animal envenomation (11). In particular, patients with HIV present an increased risk of AKI resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections (12). As an example, a recent study conducted in Sudan showed a higher mortality AKI-related mortality in females and in patients with pre-renal AKI and intoxications (13).

Since AKI is mostly preventable and treatable with limited, if any, long-term health consequences, early diagnosis and treatment are crucial to reduce the burden of disease. In this sense, Medics for Humanity is already working in The Gambia to sensitize local communities about AKI by increasing awareness, providing better education for healthcare workers, and collecting clinical data.

Chronic kidney disease (CKD)

CKD is usually caused by a long-term disease, such as diabetes or hypertension, that slowly damages the kidneys and reduces their function over time. CKD is not uncommon, and it has been estimated that it is present in almost 17% of the US population (1). CKD is defined as abnormalities of kidney structure or function, present for more than three months, with implications for health.

 

The criteria for CKD definition include the presence of kidney damage with urinary albumin excretion over 29 mg/day or decreased kidney function with GFR under 60 mL/min/1.73 m2 for three or more months (14). CKD can be classified based on the six GFR stages and the three albuminuria stages (Table 1). One of the main challenges for the identification of CKD is the fact that symptoms may not develop until very little kidney function remains, greatly complicating its management. Clinical manifestations include edema and hypertension. Signs of advancing CKD include swollen ankles, fatigue, difficulty concentrating, decreased appetite, blood in the urine and foamy urine (15). Moreover, CKD can lead to complications associated with kidney failure and others such as anemia and hyperphosphatemia (3). Undetected CKD causes a progressive loss of kidney function that can lead to kidney failure (end-stage renal disease) which requires regular dialysis treatment or a kidney transplant. CKD increases the risk of premature death from associated cardiovascular disease. Early detection and management of CKD slows or interrupts the deterioration of the kidney and diminishes the risk of associated cardiovascular complications (15).

For the diagnosis of CKD, laboratory tests are essential, being increased serum creatinin and urea concentration among the most common findings. Moreover, hyperphosphatemia, hyperkalemia, hypocalcemia, elevated parathyroid hormone, and metabolic acidosis may also be observed (1). If there is a suspect of CKD, further assessments including ultrasound, urinalysis with microscopy, and albumin to creatinine ratio are necessary. Ultrasound allows to evaluate potential obstructions, while urinalysis helps to discard glomerulonephritis or interstitial nephritis. If urinalysis is normal, the patient needs to be evaluated for renovascular disease and, if there is no evidence of renovascular disease as a causative factor, a kidney biopsy might be conducted, and further evaluation for renal replacement therapy applied if needed (1).

Table 1. Stages of chronic kidney disease (CKD) according to KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Adapted from (15). Abbreviations: GFR, glomerular filtration rate; ESRD, end-stage renal disease.

StageDescriptionGFR Level
Normal kidney functionHealthy kidneys≥90 mL/min
Stage 1Kidney damage with normal or high GFR≥90 mL/min
Stage 2Kidney damage and mild decrease in GFR60-89 mL/min
Stage 3Moderate decrease in GFR30-59 mL/min
Stage 4Severe decrease in GFR15-29 mL/min
Stage 5 (ESRD)Established kidney failure<15 mL/min or on dialysis

The two leading causes of CKD are diabetes and hypertension, which were responsible for around 75% of kidney failure cases between 2014 and 2016 (16). These two conditions are also responsible for a high proportion of end-stage kidney disease cases: 45% of new end-stage kidney disease patients were diabetic, while an additional 29% had a primary diagnosis of hypertension (16). Glomerulonephritis is the third main cause of CKD, and other etiologies include inherited diseases, such as polycystic kidney disease; birth malformations; lupus and other immune diseases; obstructions such as renal calculi or an enlarged prostate; and repeated urinary tract infections (16).

In diabetics, chronically high blood glucose levels can damage several internal organs, including the kidneys. Diabetic nephropathy is a form of CKD characterized by persistent albuminuria in the blood at levels in excess of 300 mg/day or 300 μg/min that is confirmed on at least two occasions 3-6 months apart, a progressive decline in GFR, and elevated arterial blood pressure (17). Diabetic nephropathy is one of the long-term complications associated with higher morbidity and mortality in patients with diabetes (17). The physiopathological mechanisms of diabetic nephropathy include a complex interplay of metabolic factors -glucose-dependent pathways, such as advanced glycation end-products and their receptors- and hemodynamic factors -for example vasoactive hormones, such as the components of the renin-angiotensin system (18).

Management of CKD involves treatment of reversible causes, preventing or slowing the progression of renal disease, treatment of the complications of the renal failure, medication adjustment, and proper patient’s education on the renal disease and the possibility of needing renal replacement therapy (1). Simple treatments can slow the progression of kidney disease, prevent complications and improve quality of life. In the case of diabetic nephropathy, achievement of optimal glycemic and blood pressure control in order to slow the progression are crucial, in addition to administration of specific inhibitors of the various pathways (18). In particular, agents that interrupt the renin-angiotensin system have shown a renoprotective effect in both hypertensive and normotensive type 1 and type 2 diabetic subjects (18).

Epidemiology of CKD

In the 2010 Global Burden of Disease study, CKD ranked 27th in the list of causes of total number of deaths worldwide in 1990, but rose to 18th in 2010 and to 13th in 2013 (19,20). CKD results in almost one million deaths worldwide per year, and is the direct cause of one out of 57 fatal outcomes. Kidney disease is closely associated with heart and blood vessel disease, and 7% of all cardiovascular deaths can be attributed to reduced GFR, a principal marker of CKD (20). But CKD also has a strong impact on morbidity and non-fatal outcomes, being the 15th and 20th leading causes of years lived with disability and DALYs (20).

It is estimated that about one in ten people have some degree of CKD, with a higer risk in African Americans, Hispanics, American Indians, and South Asians in part due to high rates of diabetes and high blood pressure in these communities (15). Although CKD can develop at any age, it becomes more common with increasing age since kidney filtration begins to fall by approximately 1% per year after the 40 years of age. Furthermore, several conditions damaging the kidneys are more common in older people including diabetes, high blood pressure and heart disease. It is estimated that about one in five men and one in four women between the ages of 65 and 74, and half of people aged 75 or more have CKD (15).

HIV-positive individuals are at increased risk of CKD development and progression, due to both HIV-related and traditional CKD risk factors. With prolonged longevity among HIV-positive individuals, traditional CKD risk factors such as hypertension and diabetes are of increasing concern also in HIV patients. Frequent co-infections such as hepatitis B and C viruses are associated with a 2- to 3-fold increased risk of progressive, with other co-infections such as tuberculosis and syphilis also contributing to CKD risk (12).

CKD poses a huge economic burden to the health systems, in particular patients with end-stage renal disease that require dialysis or kidney transplantation, which are highly costly. For example, in the United Kingdom, CKD treatment costs more than breast, lung, colon and skin cancer combined. In the USA, the end-stage renal disease program consumes around 7% of the total Medicare budget for less than 1% of the covered population. In China, estimations predict a lost of US$558 billion over the next decade due to effects on death and disability attributable to chronic cardiovascular and renal diseases (15).

Over 80% of individuals receiving renal replacement therapy live in high-income countries, the majority treated in only five countries -the USA, Japan, Germany, Brazil, and Italy (19). In middle-income countries, access to therapy has progressively increased in the last years, although renal replacement therapy remains unaffordable for the majority of patients. For example, in countries such as India and Pakistan, less than 10% of all patients who need it receive any kind of renal replacement therapy. In low-income countries the situation is even worst with little or none access to renal replacement therapy, leading to around one million annual deaths due to untreated kidney failure (15). The lack of availability of renal replacement therapy results in thousands of preventable deaths every year, many of them in children with diarrheal diseases and women with complications of pregnancy in low- and middle-income settings. In many countries, the medical personnel responsible for managing CKD is scarce, and has to be strengthened, as Medics for Humanity is doing in The Gambia.

In Sub-Saharan Africa, CKD constitutes a major health challenge. The overall prevalence according to a meta-analysis from 2016 was 15.8% for CKD stages 1-5 and 4.6% for CKD stages 3-5 in the general population (21). In addition to HIV infection, the major risk factors for CKD in Africa are hypertension (that affects around 25% of the adult population), glomerulonephritis, and diabetes mellitus (almost 10 million people affected in the continent) (22). Although data are very inconsistent, the prevalence of CKD in the high-risk groups may range from 1% to 46% in patients with HIV, from 11% to 90% in patients with diabetes, and from 13% to 51% in patients with hypertension (23). The main challenges for CKD management in the African continent include the increasing obesity rates due to lifestyle changes, the link between HIV and kidney failure, and treatment failures (24). The dialysis treatment rate in Sub-Saharan Africa was <20 per million population (and nil in many countries) according to a study from 2013, with in-center hemodialysis being the modality of renal replacement therapy for the majority (24). Transplantation is performed only in a few countries, including South Africa, Sudan, Nigeria, Mauritius, Kenya, Ghana, and Rwanda (24). These data highlight the urgent need for improved healthcare access and management of renal diseases in the great majority of African countries.

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