Introduction

Definition of papillary necrosis

Overview of renal papillary necrosis (RPN) as a kidney disorder

Renal papillary necrosis is not considered a disease but a condition where the renal papillae of the kidney are damaged due to necrosis(not enough blood reaching them). 

Lots of diseases and conditions can lead to renal papillary necrosis like diabetes, sickle cell disease, tuberculosis (a lung disease), pyelonephritis (an infection transmitted from the urinary tract to the kidney), renal vein thrombosis (obstruction of the kidney veins), obstructive neuropathy and overuse or abuse of some drugs.¹

Importance of drug-related causes in the condition

Anything to be excreted through the kidneys goes through three processes: glomerular filtration where the wastes to be excreted are filtered according to size, tubular reabsorption where some nutrients are reabsorbed due to their importance to the body and tubular secretion where the final products are excreted through urine.⁵

Some drugs have nephrotoxic properties where they harm the tubular cells of the kidneys so the overuse of these drugs can cause lots of harm to the kidneys like papillary necrosis.⁵

Renal papillae: function

Role in urine concentration and excretion

The renal papillae contract with a peristalsis movement  from 2 to 3 movements per minute to help collect the urine after it is filtered to pass through the renal tubules and ducts to go through the reabsorption process and then to the secretion process.²

Blood supply and vulnerability to ischemia

The kidneys, like any other organ in the body, have their own blood supply. When inflammation occurs in the kidneys, it can put pressure on the blood vessels supplying them, potentially leading to ischemia..¹

If the cause of the ischemia was corrected within a proper time and the circulation went back to normal then the kidneys and the papillae can recover but if this doesn't happen then it will lead to necrosis which is the death of the cells and tissues which is not reversible.¹

Normal physiology vs. pathology in necrosis

The renal medulla and papilla are the two parts of the kidney that can easily be exposed to ischemia and necrosis because of their complicated blood supply arrangement.¹

Even if the person is completely healthy both the renal medulla and papilla have low oxygen supply because the blood flow reaching them is slow so any disease or condition that affects their blood supply can easily cause ischemic necrosis.¹

So what happens to the papilla if it is exposed to necrosis?

When the papilla becomes necrotic, it either gets dry and tears away, leaving a space in the kidney or remains attached and then calcifies, which can cause further complications like obstructing the ureter.¹

Papillary calcification is common in patients who overuse analgesics.¹

Aetiology of papillary necrosis

Drug-related causes

It is worth mentioning that even though when renal papillary necrosis was first described it was associated with diabetes and both urinary tract infection and obstruction but its most common cause is analgesic overuse especially non-steroidal anti-inflammatory drugs like ibuprofen.³

Drug-induced renal papillary necrosis is more common in England and Australia, and more common in females than males.³

NSAIDs (nonsteroidal anti-inflammatory drugs)

Usually when patients abuse combined analgesics (more than one type of analgesic) they are the ones who are exposed the most to renal papillary necrosis.

We need to know that till now the complete mechanism of how analgesics cause renal papillary necrosis is not known. Still, there have been several well-documented studies showing that analgesics harm the interstitial cells in the renal medulla and thus inhibit some of the functions of these cells including the synthesisation of prostaglandins.³

The damage that analgesics cause to these interstitial cells negatively affects the kidney's ability to concentrate urine which is one of the signs of renal papillary necrosis.

Another effect of analgesics is that they inhibit the production of prostaglandins by affecting the cyclooxygenase enzyme.³

So by inhibiting two ways to produce prostaglandin, which is a very important protein in the body, this leads to vasoconstriction(constriction of the vessels) then ischemia and necrosis.³

Other studies showed that NSAIDs can act directly on endothelial cells ( cells of blood vessels) causing their damage which leads to ischemic necrosis.³

The effect of the overuse of NSAIDs does not stop at renal papillary necrosis, it can lead to carcinomas in the renal pelvis.³

Analgesic nephropathy

Analgesic nephropathy is a slow progressive condition where the kidneys develop papillary necrosis.⁴

It is not linked with just the use of analgesics but rather the combination of two analgesics. Also, analgesics that are combined with caffeine or codeine can cause analgesic nephropathy.⁴

Analgesics like phenacetin are considered nephrotoxic as it has a direct negative effect on the kidneys.⁴ 

Even the overuse of aspirin or paracetamol rarely causes renal diseases.⁴

Antibiotics

Nephrotoxic effects of some antibiotics (e.g., vancomycin)

Aminoglycosides

Aminoglycosides are nephrotoxic antibiotics and they are one of the most studied drugs when it comes to nephrotoxicity.⁵

Studies have shown that aminoglycosides are entirely excreted by the kidneys through glomerular filtration. They then pass through the tubular cells, where high concentrations of aminoglycosides accumulate. Notably, this is where 40% of renal necrosis occurs.⁵

This makes Aminoglycosides interfere with important renal pathways like protein reabsorption and synthesis.⁵

Vancomycin

Vancomycin is another antibiotic that was proven nephrotoxic.⁵

Its nephrotoxicity increases when the dose is more than 10 mg/L or when it is used with Aminoglycosides. In these cases, its nephrotoxicity increases 8 times.⁵

A study showed that its toxicity increases when it is taken in the afternoon compared to when it is taken in the morning.⁵

Cephalosporins

All derivatives of cephalosporins antibiotics are nephrotoxic and cause renal damage when their concentrations increase in the renal tubules it causes damage and interferes with the tubular secretion and reabsorption processes.⁵

Non-drug causes

Some diseases are associated with papillary necrosis: 

Diabetes mellitus

Patients with diabetes usually have renal tract infections and in diabetic patients, infections aren't easy to eradicate causing these infections to last longer and affect the kidneys.

Sickle cell disease

Ischemia and a decrease in the blood flow to the medulla in sickle cell disease is the reason behind papillary necrosis in sickle cell patients

Pyelonephritis

It is a kidney infection that can lead to papillary necrosis and further complications

Clinical presentation

Symptoms and signs

Hematuria (blood in urine)

Blood in urine and evidence of red blood cells and white blood cells in urine are common symptoms of papillary necrosis conditions.⁶

Flank pain

Flank or abdominal pain and colic are also common symptoms of papillary necrosis. 

It occurs due to the renal obstruction that happens due to the presence of sloughed papilla which may also calcify.⁶

Fever 

Hematuria, flank pain and fever are the trios of papillary necrosis.

Patients usually have fever and chills associated with papillary necrosis.⁶

Complications

Obstruction of the urinary tract by sloughed papillae

When the papilla gets necrotic it usually sloughs or calcifies and mimics stones in the kidneys and both scenarios can lead to obstruction of the urinary tract.⁶

Diagnosis

Diagnosis of drug-induced renal papillary necrosis when it has just started is a bit difficult because the signs and symptoms are not specific at this stage.

But later on, some signs and symptoms and other manifestations can help diagnose it.

The symptoms are flank pain, hematuria, fever and pyelonephritis. Later on, patients can suffer from hypertension, vascular diseases, cardiac diseases, and stones in the kidneys and bladder; this can even lead to renal failure.³

Laboratory findings

Hematuria, pyuria, proteinuria

Urinalysis will find evidence of:

1. blood in urine indicating hematuria.
2. protein in urine indicating proteinuria which means the protein reabsorption process was affected.
3. bacteria in blood indicating bacteriuria which means there is evidence of infection.
4. pus in urine indicating pyuria which also means there is an infection.
5. A decrease in the rate of glomerular filtration
6. Acidic renal tubules and acidic urine

Radiology 

Radiology in a condition like renal papillary necrosis is not helpful in diagnosis also magnetic resonance(MRI) is not helpful as well.

Ultrasound and computerised tomography(CT scan) are very sensitive and helpful in the diagnosis.

Treatment and management

Discontinuation of causative drugs

Withdrawal of NSAIDs or nephrotoxic agents

In drug-induced renal papillary necrosis of course the first thing to do to treat it is stopping the nephrotoxic drug.⁶

Supportive care

Hydration and management of underlying conditions (e.g., diabetes)

Since the reason leading to necrosis is ischemia therefore administering fluid is a must and also respiratory support to make sure the oxygen level in blood is optimal.⁶

Treating any underlying disease that can lead to renal papillary necrosis like Diabetes.⁶

Urine alkalinization and broad-spectrum antibiotics to eliminate the bacteria and infection.⁶