Unusual Causes of Kidney Disease: Searching for ‘Zebras’

An old adage physicians are taught is that when they hear hoofbeats, they should think of “horses,” not “zebras.” Instead of an unusual explanation for the symptoms, it’s preferable to consider more run-of-the-mill conditions.

Although that may hold true in most cases, when it comes to kidney disease and injury, physicians are advised to never keep “zebras” too far from their mind.

The upsides of this approach were on display in a recent NBC News report, which described a young woman who presented to the emergency department (ED) with serious gastrointestinal symptoms after eating a contaminated sandwich at McDonald’s. She was infected with Escherichia coli (E coli), which affected her kidneys to the point she developed hemolytic uremic syndrome and required dialysis. The presence of kidney damage did not emerge until a second ED visit, following deterioration in her condition after she returned home.

Stories like this suggest that kidney injury may be an unusual but serious complication of an apparently unrelated condition.

“When I was in training, we didn’t think about acute kidney injury (AKI) happening in an outpatient setting,” Joseph Vassalotti, MD, chief medical officer of the National Kidney Foundation, told Medscape Medical News. He noted that he couldn’t accurately comment on a case he wasn’t personally involved with but said this recent news story could remind us that “in general, acute illness should be considered an opportunity to test for kidney diseases.”

Mark Perazella, MD, professor emeritus of medicine, Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, agreed, although he clarified that kidney diseases caused by conditions other than the very most common (particularly diabetes and hypertension) aren’t “zebras, per se.” Many of the diseases aren’t actually exotic or extremely rare, but their impact on the kidneys may simply be less common than their impact on other organs.

A range of conditions can cause AKI — defined as “sudden loss of excretory kidney function,” chronic kidney disease (CKD), or renal failure, even if the kidneys aren’t the most commonly affected organs (Table 1).

Wide Range of Infectious Causes

The young woman who ate the contaminated McDonald’s sandwich was infected with Shiga toxin–producing E coli, which can lead to hemolytic uremic syndrome, kidney failure, and potentially death. This is one of the four groups of E coli that cause diarrhea in people infected through ingesting contaminated food or water or through some other fecal-oral route. Symptoms include diarrhea (with or without blood), abdominal cramping, nausea, headache, vomiting, and fever. The clinical presentation of hemolytic uremic syndrome usually includes blood in the urine or stool, severe oliguria hematuria, microangiopathic hemolytic anemia, hypotension, and perhaps neurologic changes.“Someone who presents with these symptoms should get a more extensive workup that includes electrolyte and kidney function testing, as well as receiving IV fluids, since most cases of viral gastroenteritis or food poisoning shouldn’t cause such a severe presentation,” said Vassalotti, who is also clinical professor at Icahn School of Medicine at Mount Sinai, New York City. If a clinician sees more than one patient with a similar presentation, “that would be another hint” that a foodborne pathogen might be responsible and to investigate kidney function. “Think about clusters of presentations,” Vassalotti advised.

“Other symptoms that might suggest a kidney problem include swelling, loss of appetite, nausea, and polyuria,” Perazella noted.

“Ironically, antibiotics aren’t helpful with this condition,” Vassalotti pointed out. “Instead, treatment is usually focused on fluid resuscitation for loss of volume primarily from diarrhea and vomiting and supportive care. If there’s sufficient kidney damage — as in the case of the woman in the article — the patient may require dialysis. Hopefully, the kidney function will recover and resolve, but that doesn’t always happen.”

Perazella urged clinicians to bear in mind that many infections can cause both acute and chronic kidney damage, “although more acute than chronic.” Infections can be bacterial, viral, fungal, and parasitic. Renal involvement is more often a minor component of systemic infections. But sometimes, renal failure may actually be the first presenting feature or the most serious outcome.

Table 2 lists systemic infectious causes of renal dysfunction. Infections can also be focal and can be viral, parasitic, or fungal (Tables 3 and 4).

Chronic pulmonary infections, such as bronchiectasis, can lead to deposits of amyloid in various structures within the kidney, ultimately causing damage.

What Medications Is the Patient Taking?

Many common and less commonly prescribed medications can cause AKI or CKD (Table 5).

Perazella explained that direct acute tubular injury develops from medications that are “toxic to various cellular functions.” Drug-induced AKI may also be caused through “induction of inflammation within the tubulointerstitium.” 

A less-common pathway occurs when drugs that are insoluble in urine form crystals within distal tubular lumens. In this setting, AKI is caused by intratubular obstruction, direct tubular injury, and localized inflammation.

It’s important to distinguish between AKI and pseudo AKI, characterized by an acute increase in serum creatinine that occurs independently of change in glomerular filtration rate and can be caused by medications that decrease tubular secretion of creatinine.

Be vigilant regarding PPIs, which are among the most commonly dispensed drugs in the United States, with one tenth of all ambulatory care patients having documented PPI use. At each primary care visit, indications for long-term PPI use should be addressed to avoid potential kidney damage.

A multidisciplinary team approach, which might include not only the prescribing physician but also a pharmacist, can improve patient care and facilitate decision-making when discontinuing medication use or selecting a more appropriate dose.

Certain herbal remedies (eg, those containing aristolochic acid) have been reported to cause kidney abnormalities, These are found particularly in Chinese herbal preparations. Other products used in complementary/alternative medicine (CAM) may contain undisclosed drugs or unknown compounds. An increasing number of patients are relying on CAM without sharing this information with their physician, so patients should be asked about use of CAM products and physicians should be familiar with potential hazards.

Current or Previous History of Cancer

Cancer and its treatments (chemotherapy, immunotherapy, chimeric antigen receptor T cells, and stem cell transplants) can cause acute and CKD Critically ill patients with cancer are at the highest risk for AKI, with an incidence of up to 54%, especially in patients with hematologic cancers, multiple myeloma, and septic shock.

Autoimmune, Genetic, and Other Conditions

Perazella noted that several autoimmune conditions can affect the kidneys. Glomerular, tubular, and vascular structures can all be damaged by autoimmune processes. Although the autoantigens themselves may be nonrenal, they can become renal targets.

Alterations in kidney function have been identified in autoimmune connective tissue diseases — for example, Sjögren syndrome, systemic scleroderma, autoimmune myopathies (dermatomyositis and polymyositis), systemic lupus erythematosus, antiphospholipid syndrome nephropathy, and rheumatoid arthritis. In these conditions, renal biopsy is necessary to ensure diagnosis when patients present with deterioration in renal function, increase in proteinuria, or signs of nephritic syndrome. It’s advisable for these patients to be treated using a multidisciplinary approach.

Diseases that affect the joints, such as rheumatic fever and scarlet fever, can also negatively affect the kidneys, Perazella stated.

Genetic conditions, present in roughly 10% of adults and almost all children who require renal replacement therapy, can also cause renal failure. Common monogenic diseases include polycystic kidney disease, Alport syndrome, and Fabry disease, as well as complex disorders such as congenital anomalies of the kidney and urinary tract. According to a recent review, genetic kidney diseases cause the majority of cystic kidney diseases and tubulopathies, several congenital abnormalities of the kidney and urinary tract, and select glomerulopathies. These diseases are identified more frequently in children and have only recently emerged as culprits in CKD in adults.

In Black individuals, mutations in the APOL1 gene (APOL1-mediated kidney disease) increase rates of hypertension-associated end-stage kidney disease, HIV-associated nephropathy, focal segmental glomerulosclerosis, and other types of kidney disease not associated with diabetes.

Individuals of West African heritage with nondiabetic CKD, proteinuria, or a family history of kidney disease may be offered APOL1 screening. In people with a high-risk genotype, physicians may want to consider more frequent screening for reduced glomerular filtration rate and proteinuria to identify the condition at an early stage.

Perazella added that liver disease, especially in end stages, can affect the kidneys. “We often see patients in the hospital or clinic who have both liver and kidney disease — hepatorenal syndrome — and they may need a liver transplant, as well as dialysis, due to renal failure.” 

Clinicians should be attuned to potential kidney involvement in patients with thyroid conditions (hypothyroidism and hyperthyroidism), which can occur both directly and through systemic hemodynamic, metabolic, and cardiovascular affects.

Tips for Non-Nephrologists

A patient who presents to the ED with swelling, anorexia, and nausea, as well as fever of unknown origin, should be evaluated for potential renal conditions, Perazella advised. This also applies to individuals with cancer, rheumatologic disease, and other conditions that might cause renal damage.

“In acute kidney injury, patients may feel and even lookterrible, and that’s a clue as well,” he observed.

Vassalotti noted that hypotension symptoms should prompt suspicion to test kidney function. Additionally, “ask patients if they’ve traveled recently, especially to areas where diseases such as malaria are endemic,” he advised. If kidney disease is suspected and lab tests confirm the suspicion, a nephrologist should be consulted.

In patients with CKD, a nephrologist should be consulted when the patient has an estimated glomerular filtration rate 2, severe albuminuria, and AKI, and when the cause of kidney disease is not clear. Knowing the cause informs prognosis and interventions, Vassalotti said.

As noted by the authors of a 2020 study, nephrologists can help “slow the progression of CKD, educate patients regarding the optimal choice of kidney failure replacement therapy…assess medication dosage and safety, and assist primary care providers with management of hypertension, cardiovascular disease risk factors, anemia, and bone and mineral health.” 

Timely referral to a nephrologist improves outcomes, including disease-related comorbidities and survival, Vassalotti added. Primary care clinicians and nephrologists should continue to collaborate in the patient’s care. Together, they can work to identify the rare “zebras” that are present in their clinics.

Vassolotti and Perazella reported no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape Medical News and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told their story).