Nephropathy: Definition, Types, Symptoms, Risk Factors, Diagnosis, Treatment and Prognosis

It is a broad medical term used to denote kidney disease or damage, which can eventually lead to kidney failure.

The kidney’s primary and most apparent functions are to excrete any waste products and regulate the water and acid-base balance of the body; therefore, loss of kidney function is a life-threatening condition.

Nephropathy is considered a progressive disease; in other words, as the kidneys become less and less effective over time (as the disease progresses), the patient’s condition worsens if left untreated.

This is why it is essential to receive a proper diagnosis and treatment as soon as possible.

Diabetic nephropathy

Diabetic nephropathy (DN), also known as diabetic kidney disease, is the chronic loss of kidney function in people with diabetes mellitus.

The loss of protein in the urine due to damage to the glomeruli can become massive and cause low serum albumin, resulting in generalized swelling of the body (edema) and nephrotic syndrome.

Likewise, the estimated glomerular filtration rate (eGFR) can progressively decrease from a normal of more than 90 ml/min / 1.73 m2 to less than 15, at which point the patient is said to have the end-stage renal disease ( ESKD). It is usually slowly progressive over the years.


The pathophysiologic abnormalities in diabetic nephropathy begin with long-standing poorly controlled blood glucose levels. This is followed by multiple changes in the kidney’s filtering units, the nephrons.

There usually are around 750,000-1.5 million nephrons in each adult kidney. Initially, the efferent arterioles constriction and dilation of the afferent arterioles, resulting in glomerular capillary hypertension and hyperfiltration; this gradually changes to hyperfiltration over time.

At the same time, there are changes within the glomerulus: these include a thickening of the basement membrane, a widening of the membranes of the podocyte clefts, an increase in the number of mesangial cells, and an increase in the mesangial matrix.

This matrix invades the glomerular capillaries and produces deposits called Kimmelstiel-Wilson nodules. Mesangial cells and matrix can progressively expand and consume the entire glomerulus, closing the filtration.

The state of diabetic nephropathy can be controlled by measuring two values: the amount of protein in the urine – proteinuria; and a blood test called serum creatinine.

The amount of proteinuria reflects the degree of damage to any glomeruli still functioning. The serum creatinine value can calculate the estimated glomerular filtration rate (eGFR), which reflects the percentage of glomeruli that no longer filter the blood.

Treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), which dilates the arteriole exiting the glomerulus and lowers blood pressure within the glomerular capillaries, can slow (but not stop ) disease progression.

Three classes of diabetes medications, GLP-1 agonists, DPP-4 inhibitors, and SGLT2 inhibitors, are also believed to slow the progression of diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage kidney disease and is a severe complication that affects approximately a quarter of adult diabetics in the United States.

People affected with end-stage kidney disease often require hemodialysis and a kidney transplant to replace failed kidney function. Diabetic nephropathy is associated with an increased risk of death, particularly from cardiovascular diseases.


The pathophysiology of the glomerulus in diabetic nephropathy can be better understood by considering the three cells involved as a unit: the endothelial cell, the podocyte, and the mesangial cell.

These cells are in physical contact with each other at various places within the glomerulus; they also communicate chemically at a distance. All three compartments are abnormal in diabetic nephropathy.

Diabetes causes changes in the body’s metabolism and blood circulation, which probably combine to produce excess reactive oxygen species (chemically reactive oxygen-containing molecules).

These changes damage the kidney’s glomeruli (networks of small blood vessels), leading to the distinctive feature of albumin in the urine (called albuminuria).

As diabetic nephropathy progresses, a structure in the glomeruli known as the glomerular filtration barrier (GFB) becomes increasingly damaged.

This barrier comprises three layers: the fenestrated endothelium, the glomerular basement membrane, and the epithelial podocytes.

The glomerular filtration barrier is responsible for the highly selective filtration of blood entering the kidney’s glomeruli. It usually only allows the passage of water, small molecules, and tiny proteins (albumin does not pass through the intact glomerular filtration barrier ).

Damage to the glomerular basement membrane allows proteins in the blood to leak out, leading to proteinuria.

The deposition of abnormally large amounts of mesangial matrix causes positive periodic acid Schiff nodules called Kimmelstiel-Wilson nodules.

High blood sugar leads to the formation of advanced glycation end products, and cytokines have also been implicated as mechanisms for developing diabetic nephropathy.

Another relevant factor is diabetes-induced hypoxia, which is an aggravating factor since it increases interstitial fibrosis, partly due to the induction of the synthesis of TGF-β and vascular endothelial growth factor (VEGF), which is mediated by hypoxia-inducing factor- 1.

Hypoxia can activate fibroblasts and alter the metabolism of the extracellular matrix of resident renal cells.

Leading to final fibrogenesis and even mild hypoxia can induce transdifferentiation of cultured tubular cells into myofibroblasts.

This leads to a vicious cycle with hypoxia promoting interstitial fibrosis and increased matrix deposition; it further affects peritubular blood flow and oxygen supply.

Signs and symptoms

The onset of symptoms is 5 to 10 years after the disease begins. A typical first symptom is a frequent urination at night: nocturia.

Other symptoms include tiredness, headaches, general ill feeling, nausea, vomiting, frequent urination during the day, poor appetite, itchy skin, and swollen legs.

Risk factor’s

The incidence of diabetic nephropathy is higher in people with diabetes with one or more of the following conditions:

  • Poor blood glucose control.
  • Uncontrolled hypertension.
  • Type 1 diabetes mellitus, with onset before the age of 20.
  • Use of cigarettes in the past or present.
  • A family history of diabetic nephropathy.


The diagnosis is based on the measurement of abnormal urinary albumin levels in a person with diabetes and the exclusion of other causes of albuminuria. Albumin measurements are defined as follows:

Normal albuminuria: urinary albumin excretion <30mg / 24 h.

Microalbuminuria: urinary albumin excretion in 30-299 mg / 24 h.

Macroalbuminuria : urinary albumin excretion ≥ 300mg / 24 h.

It is recommended that people with diabetes have their albumin levels checked annually, beginning immediately after a type 2 diabetes diagnosis and five years after a type 1 diabetes diagnosis.

Medical imaging of the kidneys, usually by ultrasonography, is recommended as part of a differential diagnosis in the case of suspected urinary tract obstruction, urinary tract infection or kidney stones, or polycystic kidney disease.


To assess the degree of damage in this (and any) kidney disease, serum creatinine is determined and used to calculate the estimated glomerular filtration rate (eGFR). The estimated average glomerular filtration rate is equal to 90ml / min / 1.73m2.


The treatment goals are to slow the progression of kidney damage and control related complications.

The primary treatment, once proteinuria is established, is ACE inhibitor drugs, which generally reduce proteinuria levels and slow the progression of diabetic nephropathy.

Other problems that are important in managing this condition include controlling high blood pressure and blood sugar levels and reducing dietary salt intake.


Diabetic nephropathy in type 2 diabetes can be more challenging to predict because the onset of diabetes is often not well established. Without intervention, 20-40 percent of type 2 diabetes/microalbuminuria patients will progress to macroalbuminuria.

Diabetic nephropathy is the most common cause of end-stage kidney disease, which may require hemodialysis or even kidney transplantation. It is associated with an increased risk of death, particularly from cardiovascular disease.


In the US, diabetic nephropathy affected approximately 6.9 million people from 2005-to 2008. Consequently, the number of people with diabetes and diabetic nephropathy is expected to increase substantially by 2050.

Immunoglobulin A (IgA) nephropathy

Immunoglobulin A nephropathy (IgA nephropathy), also known as immunoglobulin A nephritis, Berger’s disease (/ bɛərʒeɪ /) (and variations), or sympharyngitic glomerulonephritis.

It is kidney disease (or nephropathy); specifically, it is a form of glomerulonephritis or inflammation of the kidney’s glomeruli.

Immunoglobulin A nephropathy is the most common glomerulonephritis worldwide. Primary immunoglobulin A nephropathy is characterized by the deposition of the immunoglobulin A antibody in the glomerulus.

There are other diseases associated with glomerular immunoglobulin A deposits, the most common of which is immunoglobulin A vasculitis, formerly known as Henoch-Schönlein purpura (PHS), which many consider be a systemic form of immunoglobulin A nephropathy.

Immunoglobulin A vasculitis presents with a characteristic purple skin rash, arthritis, and abdominal pain and occurs most often in young adults (16-35 years).

Henoch-Schönlein purpura is associated with a more benign prognosis than immunoglobulin A nephropathy. In immunoglobulin A nephropathy, there is a slow progression to chronic renal failure in 25-30% of cases over 20 years.

Signs and symptoms

The classic presentation (in 40-50% of cases) is episodic hematuria, which usually begins within a day or two of a nonspecific upper respiratory tract infection (therefore lymphangitic), as opposed to post-streptococcal glomerulonephritis, which occurs time (weeks) after the initial infection.

Less commonly, the gastrointestinal or urinary infection may be the inciting agent. All these infections have in common the activation of the mucosal defenses and, therefore, the production of immunoglobulin A antibodies. Pain in the groin can also occur.

Gross hematuria resolves after a few days, although microscopic hematuria may persist. These episodes occur irregularly every few months and, in most patients, eventually diminish, although it can take many years.

Kidney function generally remains normal, although acute kidney failure can rarely occur (see below). This presentation is more common in young adults.

A smaller proportion (20-30%), generally the older population, have microscopic hematuria and proteinuria (less than 2 grams/day). These patients may not have any symptoms and are only found clinically if a doctor decides to take a urine sample.

Therefore, the disease is most commonly diagnosed when urine testing is mandatory (for example, in school-age children in Japan). Very rarely (5% each), the presentation story is:

Nephrotic syndrome : 3-3.5 grams of protein loss in the urine, associated with a poorer prognosis.

Acute renal failure: either as a complication of frank hematuria, when it usually recovers, or rapidly progressive glomerulonephritis that often leads to chronic renal failure.

Chronic renal failure: without previous symptoms, presents with anemia, hypertension, and other signs of renal failure, in people who probably had microscopic hematuria and proteinuria not detected for a long time.

Many systemic diseases are associated with immunoglobulin A nephropathy, including liver failure, celiac disease, rheumatoid arthritis, reactive arthritis, ankylosing spondylitis, and HIV.

The diagnosis of immunoglobulin A nephropathy and the search for any associated disease sometimes reveals an underlying severe systemic illness.

Occasionally, there are concurrent symptoms of Henoch-Schönlein purpura. Some HLA alleles have been suspected and complement phenotypes as genetic factors.


Histologically, immunoglobulin A nephropathy may show mesangial widening and focal segmental inflammation. There may also be diffuse mesangial proliferation or crescentic glomerulonephritis.

Immunofluorescence shows mesangial deposition of immunoglobulin A often with C3 and properdin and smaller amounts of other immunoglobulins (IgG or IgM). The first components of the classical complement pathway (C1q or C4) are usually not seen.

Electron microscopy confirms dense electron deposits in the mesangium that can spread to the subendothelial area of ​​the adjacent capillary walls in a small subset of cases, generally those with focal proliferation.


The disease derives its name from immunoglobulin A (IgA) deposits in a granular pattern in the mesangium (by immunofluorescence), a region of the renal glomerulus. The mesangium by light microscopy may be hypercellular and show a more significant deposition of extracellular matrix proteins.

Regarding the renal manifestation of Henoch-Schönlein purpura, it has been found that although it shares the same histological spectrum as immunoglobulin A nephropathy, a higher frequency of severe lesions, such as glomerular necrosis and crescents, was observed.

Consequently, Henoch-Schönlein nephritis purpura has a higher frequency of glomerular staining for fibrin than immunoglobulin A nephropathy but with a similar immunofluorescence profile.

There is no clear and known explanation for the accumulation of immunoglobulin A. Exogenous antigens for immunoglobulin A have not been identified in the kidney. Still, this antigen may have been cleared before the disease manifests itself.

It has also been proposed that immunoglobulin A itself may be the antigen. A recently advanced theory focuses on abnormalities of the IgA1 molecule.

IgA1 is one of two immunoglobulin subclasses (IgD) that is O-glycosylated at various serine and threonine residues in a particular proline-rich hinge region.

Aberrant glycosylation of immunoglobulin A appears to lead to the polymerization of immunoglobulin A molecules in tissues, especially the glomerular mesangium.

A similar mechanism has been claimed to underlie Henoch-Schönlein purpura. This vasculitis primarily affects children and can present with kidney involvement almost indistinguishable from immunoglobulin A nephritis.

However, human studies have found that IgA1 degalactosylation occurs in patients with immunoglobulin A nephropathy in response only to intestinal antigen (non-systemic) exposures and occurs in healthy people to a lesser extent.

This strongly suggests that IgA1 degalactosylation results from an underlying phenomenon (abnormal mucosal antigen handling) and is not the ultimate cause of immunoglobulin A nephropathy.

Evidence suggests that both galactose-deficient o-glycans in the IgA1 hinge region and the synthesis and binding of antibodies against IgA1 are necessary for immunoglobulin complexes to form and accumulate in the glomeruli.

From the fact that immunoglobulin A nephropathy can recur after kidney transplantation, it can be postulated that the disease is caused by a problem in the immune system rather than the kidney itself.

Surprisingly, the IgA1 that accumulates in the kidney does not come from the mucosa-associated lymphoid tissue (MALT), which is the site of most upper respiratory tract infections, but rather from the bone marrow.

This also suggests an immune pathology rather than direct interference from external agents.

Natural History

As immunoglobulin A nephropathy generally presents without symptoms through abnormal findings on urinalysis, there is considerable potential for variation in any population studied, depending on the screening policy.

Similarly, local policy for renal biopsy assumes a critical role; if it is a policy to observe patients with isolated bloody urine, a group with a generally favorable prognosis will be excluded.

If, on the other hand, all these patients are biopsied, the group with isolated microscopic hematuria and isolated mesangial immunoglobulin A will be included, and the prognosis for that particular series will be “improved.”

However, immunoglobulin A nephropathy, which was initially thought to be a benign disease, has been shown to have not-so-benign long-term results.

Although most reports describe immunoglobulin A nephropathy as an indolent course toward scarring or kidney damage, a more aggressive approach associated with extensive crescents is sometimes seen and presents as acute renal failure.

In general, entry into chronic kidney failure is slow compared to most other glomerulonephritis, occurring on a time scale of 30 years or more (in contrast to the 5 to 15 years for another glomerulonephritis).

This may reflect the previous diagnosis made due to frank hematuria. Complete remission, that is, a routine urinalysis, rarely occurs in adults in about 5% of cases.

Thus, even in those with normal kidney function after a decade or two, urinary abnormalities persist in the vast majority.

In contrast, 30-50% of children can have a routine urinalysis by the end of 10 years. However, given the prolonged evolution of this disease, the longer-term outcome (20-30 years) of such patients has not yet been established.

Although kidney survival is 80-90% after ten years, at least 25% and perhaps up to 45% of adult patients will eventually develop end-stage renal disease.


For an adult patient with isolated hematuria, tests such as ultrasound of the kidney and cystoscopy are usually performed first to identify the source of the bleeding.

These tests would rule out kidney stones and bladder cancer, two other common urologic causes of hematuria. The history and association with respiratory infection in children and young adults may raise suspicion of immunoglobulin A nephropathy.

A kidney biopsy is necessary to confirm the diagnosis. The biopsy sample shows proliferation of the mesangium, with immunoglobulin A deposits on immunofluorescence and electron microscopy.

However, patients with isolated microscopic hematuria (without associated proteinuria and normal renal function) do not usually undergo a biopsy, which is associated with an excellent prognosis.

A urinalysis will show red blood cells, usually as urinary red blood cell casts. Proteinuria, generally less than 2 grams per day, can also be present.

Other renal causes of isolated hematuria are thin basement membrane disease and Alport syndrome, an inherited disorder associated with hearing and eye problems.


The ideal treatment for immunoglobulin A nephropathy would remove immunoglobulin A from the glomerulus and prevent another immunoglobulin A deposition.

This goal is still a remote prospect. There are some additional caveats to consider when treating immunoglobulin A nephropathy.

Immunoglobulin A nephropathy has a variable course, ranging from benign recurrent hematuria to rapid progression to chronic renal failure. Therefore, the decision about which patients to treat should be based on prognostic factors and the risk of progression.

Furthermore, immunoglobulin A nephropathy recurs in transplants despite using cyclosporine, azathioprine, or mycophenolate mofetil and steroids in these patients.

There are persistent uncertainties due to the limited number of patients included in the few randomized controlled studies.

They produce little statistically significant evidence regarding the heterogeneity of patients with immunoglobulin A nephropathy, the diversity of study treatment protocols, and the length of follow-up.

Patients with isolated hematuria, proteinuria <1g / day, and normal renal function have a benign course and are generally only followed annually.

In cases where tonsillitis is the trigger for episodic hematuria, it has been claimed that tonsillectomy reduces the frequency of these episodes.

However, it does not reduce the incidence of progressive kidney failure. Furthermore, the natural history of the disease is such that episodes of frank hematuria decrease over time, regardless of any specific treatment.

Similarly, prophylactic antibiotics are not beneficial. Dietary gluten restriction, used to reduce mucosal antigen exposure, has not been shown to preserve kidney function. Phenytoin has also been tried without any benefit.

A subset of patients with immunoglobulin A nephropathy, who have minimal change disease on light microscopy and clinically have nephrotic syndrome, show an exquisite response to steroids, behaving more or less like minimal change disease.

In other patients, the evidence for steroids is not convincing. Short courses of high-dose steroids have been shown to lack benefits.

However, in patients with preserved kidney function and proteinuria (1-3.5g / day), a recent prospective study has shown that a 6-month steroid regimen can decrease proteinuria and protect kidney function.

However, the risks of long-term steroid use must be weighed in such cases. It should be noted that the study had ten years of patient follow-up data and showed the benefit of steroid therapy.

In the steroid group, there was a lower chance of reaching end-stage renal disease (kidney function so poor that dialysis was required).

Importantly, angiotensin-converting enzyme inhibitors were used in both groups equally. Cyclophosphamide had been used in combination with anticoagulants/antiplatelets in unselected patients with immunoglobulin A nephropathy, with conflicting results.

Furthermore, the side effect profile of this drug, including the long-term risk of malignancy and infertility, made it an unfavorable option for use in young adults.

However, a recent study in a carefully selected high-risk population of patients with declining glomerular filtration rates showed a combination of steroids and cyclophosphamide for the initial three months followed by azathioprine for a minimum of 2 years resulted in a preservation function.

Other agents such as mycophenolate mofetil, cyclosporine, and mizoribine have also been tried with variable results.

A Mayo Clinic study showed that long-term treatment with omega-3 fatty acids reduces the progression to kidney failure. However, it does not minimize proteinuria in a subgroup of patients at high risk of worsening kidney function.

However, other study groups have not reproduced these results in two subsequent meta-analyses.

However, fish oil therapy does not have the drawbacks of immunosuppressive treatment. Also, aside from its unpleasant taste and abdominal discomfort, it is relatively safe to consume.

Events that tend to progressive renal failure are not unique to immunoglobulin A nephropathy, and nonspecific measures to reduce it would be equally helpful.

These include a low protein diet and optimal blood pressure control. The choice of the antihypertensive agent is open as long as the blood pressure is controlled to the desired level.

However, angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists are favored due to their anti-proteinuric effect.

Other types of kidney disease

Analgesic nephropathy is a chronic kidney disease caused by prolonged and excessive use of pain reliever mixtures containing phenacetin or two other pain relievers, such as:

Salicylic acid-paracetamol, salicylic acid-pyrazolones, paracetamol-pyrazolones, or two pyrazolones combined with potentially addictive substances such as codeine or caffeine.

Renal papillary necrosis (i.e., damage to the internal medulla caused by capillary sclerosis) represents the hallmark of analgesic nephropathy. It most often arises as a result of long-term use of phenacetin.

Renal complications are acute or chronic pyelonephritis, calcification of necrotic papillae, urolithiasis, and uroepithelial tumors.

Acute uric acid nephropathy arises from the intratubular deposition of uric acid crystals with a high serum uric acid concentration.

This condition usually occurs during induction chemotherapy for malignant tumors with high cell turnover.

Recommended treatment options for this condition are alkalinization of the urine and a drug known as rasburicase (a recombinant urate oxidase).