26th June 2023

Systemic Disorders Affecting the Kidney

Renal Involvement of Systemic Disorders

Overview

The kidneys may be directly involved in a number of diseases or affected secondarily by diseases of other organs.
Given their microcirculation, the kidneys are often susceptible to damage in other disorders which affect blood vessels. This can be due to damage to the renal glomerulus or renal tubules themselves, deposition of toxic products, or inflammation.

Renal disease is often categorised by histological findings on renal biopsy; however, in some cases, this may not be necessary as the cause of the renal disease may be obvious by the clinical findings of the causative disorder. In this section we will explore some of the chronic systemic diseases which commonly impact the kidneys.

Diabetes and the kidney

Complications of diabetes

Diabetes accounts for almost 1 in 7 deaths in the UK, and whilst the majority of these are from cardiovascular complications, diabetes is the most common cause of chronic kidney disease in the UK and the developed world.

Chronic complications of diabetes are usually categorised as microvascular or macrovascular depending on the size of the blood vessel that they affect.

The macrovascular complications are:

• Coronary artery disease
• Cerebrovascular disease
• Peripheral vascular disease.

The microvascular complications are:

• Nephropathy – kidney disease
• Retinopathy – affecting the eyes, sometimes called maculopathy
• Neuropathy – affecting both the peripheral and central nervous system

Diabetic nephropathy

Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in people with diabetes and is associated with those who have had diabetes for over ten years and those with the poorest glycaemic control. The clinical hallmark of diabetic nephropathy is the presence of proteinuria on urinalysis, which can be quantified by a urine albumin creatinine ratio (ACR) and protein creatinine ratio (PCR), leading to progressive chronic kidney disease. Both Type 1 and Type 2 diabetes have equivalent rates of proteinuria and end stage renal disease.

On renal biopsy, the pathological feature most associated with diabetic nephropathy is the presence of glomerulosclerosis. Early histopathological changes involve glomerular basement membrane thickening, mesangial expansion, and podocyte depletion, progressing to glomerulosclerosis. Few patients require renal biopsy to establish the diagnosis, however.

The renal involvement of diabetes in many diabetic patients is clinically silent and often only picked up as part of screening.

Prevention and management of diabetic complications include both non-pharmacological and pharmacological options. Lifestyle changes should be addressed in every diabetic patient, including smoking cessation, increasing exercise, as well as managing other cardiovascular risk factors such as hypertension and hyperlipidaemia. In diabetic nephropathy, good blood pressure control is important in reducing proteinuria and slowing the rate of decline of renal function. Treatment with an ACE inhibitor or angiotensin receptor blocker (ARB) should be initiated in all patients with an ACR ≥ 3mg/mmol, even if the blood pressure is normal. Tight glycaemic control through lifestyle factors and insulin/oral hypoglycaemic medications is paramount in reducing all diabetic complications.

Hypertension and the kidney

Hypertensive nephrosclerosis

Hypertension and renal disease are closely linked; renal dysfunction can develop as a result of chronic hypertension, however, hypertension can also be the result of renal disease. In some cases it can be challenging to differentiate which came first. In benign essential hypertension, arteriosclerosis of major renal arteries occurs. This change is known as nephrosclerosis. Deterioration in renal function accompanies this along with a reduction in the size of both kidneys, which may be asymmetrical if one renal artery is involved more than the other.

Patients with high blood pressure and normal renal function blood tests have a significant reduction in the number of nephrons in each kidney. To compensate for this, there is enlargement of the remaining glomeruli due to hyperfiltration. Microscopic (non-nephrotic range) proteinuria and haematuria occur, as does progressive uraemia.

If treatment of hypertension is initiated before CKD has developed, then there is good prognosis for the preservation of renal function. Patients with CKD should have a blood pressure target of less than 140/90 mmHg for a clinic reading and less than 135/85mmHg for a home or ambulatory blood pressure measurement.

Renal hypertension

Hypertension secondary to renal disease itself can be caused by conditions such as renal artery stenosis, chronic glomerulonephritis, bilateral reflux nephropathy or polycystic disease. There are two main mechanisms which are responsible for the increase in blood pressure:

1.   Activation of the renin-angiotensin-aldosterone (RAAS) system
2.   Retention of salt and water

If the renal disease in question is cortical in nature, such as in glomerulonephritis, hypertension occurs earlier, is more common, and tends to be more severe. This leads to an increase in blood volume and therefore blood pressure. Tight control of blood pressure is necessary to prevent further deterioration in renal function, and there is good evidence that ACE inhibitor treatment offers significant renal protection.

Connective Tissue Disease and the kidney

Vasculitis

Inflammation and necrosis of blood vessel walls occur in many primary vasculitic disorders. Small vessel vasculitis is often associated with kidney disease due to the susceptible microcirculation of the kidneys. On histology, there is a focal inflammatory glomerulonephritis, usually with necrosis. Typically, the patient is unwell with an acute phase response, weight loss and arthralgia. In some patients, pulmonary haemorrhage may occur and can lead to respiratory impairment and/or death.

An important cause of renal impairment to exclude is ANCA-positive vasculitis. Anti-neutrophil cytoplasmic antibodies (ANCA) can attack the kidney tissue and lead to a deterioration in function. Subtypes of ANCA-positive vasculitis include:

• MPA (microscopic polyangiitis) – typically associated with renal dysfunction from glomerulonephritis and occasionally with pulmonary haemorrhage or gastrointestinal involvement.
• Granulomatosis with polyangiitis, formerly known as Wegener’s granulomatosis – typically involves the upper respiratory tract, the lower respiratory tract, and the kidneys. Upper respiratory tract involvement typically manifests as granulomas affecting the nasal passages and sinuses, causing nasal stuffiness, crusting, and epistaxis. Lower respiratory tract involvement manifests as granulomatous lung disease causing infiltrates, cavitating lesions, and pulmonary haemorrhage.
• Eosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is another subtype of ANCA-positive small vessel vasculitis causing fever, sweating, weight loss, fatigue and hypereosinophilia. It is more common in patients with a history of allergic rhinitis and asthma. It can also be a cause of pulmonary haemorrhage.

PR3-ANCA (or cANCA) is most associated with Wegener’s granulomatosis, whereas MPO-ANCA (or pANCA) is most associated with microscopic polyangiitis. However, these are not specific, and biopsies should be obtained. Variation in the ANCA titres can be used in the assessment of disease activity.

The standard treatment of ANCA-positive vasculitis is with high dose steroids, cyclophosphamide, and mycophenolate. Glomerulonephritis secondary to vasculitis can also be seen in other conditions, such as cryoglobulinemia and SLE. Medium to large vessel vasculitis, such as polyarteritis nodosa (PAN), do not cause glomerulonephritis but can cause renal infarction if the renal blood vessels are involved.

Systemic Lupus Erythematosus

Renal disease occurs in at least 1/3rd of patients with systemic lupus erythematosus (SLE), and of these, a quarter reach end stage renal failure within ten years. SLE is a multi-system disorder affecting most body systems. SLE can also cause a clinical picture of glomerulonephritis.

The most common presentation is of a sub-acute nephritic disease with haematuria, hypertension, and renal impairment. Almost any histological pattern of glomerular disease can be seen in SLE on renal biopsy, including stains positive for IgG, IgM, IgA and complement proteins. The clinical presentation ranges from an indolent and slowing progressive nephrotic syndrome to a florid rapidly progressive glomerulonephritis requiring renal replacement therapy. Immunofluorescence staining shows substantial deposits within the glomerulus.

The classification of lupus nephritis (LN) is as follows:

Class I – minimal mesangial deposition (asymptomatic)
Class II – mesangial proliferative LN (mild renal disease)
Class III – focal LN, involving <50% glomeruli (haematuria and proteinuria)
Class IV – diffuse LN, involving >50% glomeruli (most common and severe form of LN)
Class V – membranous LN (good prognosis)
Class VI – advanced sclerosing LN >90% sclerosed glomeruli (progressive CKD)

Treatment is with high dose steroids and intravenous cyclophosphamide. Prognosis is best for patients with type I, II and V.

Malignancy and the kidney

Solid tumours

The kidney is affected by many different malignant diseases, by direct involvement of the kidneys, or indirectly by involvement of other parts of the urinary tract. The most common cause of this is obstruction from either a primary tumour or metastasis, resulting in a post-renal acute kidney injury. These tumours can include primary renal adenocarcinoma, tumours of the urothelium or bladder, or the cervix. Glomerulonephritis can also occur as a result of an immunological reaction to other tumours or also as a result of a paraneoplastic syndrome.

Hypercalcemia can occur as a paraneoplastic syndrome from a solid tumour. This frequently happens in breast cancer and lung cancer, caused by parathyroid hormone related protein (PTHrP) or secondary to bone metastasis. High levels of calcium can lead to renal complications, such as renal calculi. The acute drop of the glomerular filtration rate that also occurs as a result of hypercalcaemia is thought to be mediated by renal vasculature constriction in response to the high calcium, leading to a reduced glomerular blood flow and filtration. Hypercalcaemia is also associated with increased sodium excretion and water excretion.

Sometimes treatment of leukaemia and lymphoma, or the resultant tumour lysis syndrome with allopurinol, can be complicated by acute interstitial nephritis. Hypercalcemia caused by the release of calcium in tumour lysis syndrome can also occur in this context, as well as in plasma cell tumours such as myeloma.

Myeloma

In myeloma and other monoclonal gammopathies, renal impairment occurs as the result of the nephrotoxic effect of immunoglobulin light chains. Multiple myeloma is a malignant proliferation of plasma cells. Normal plasma cells come from the B cell line and produce immunoglobulins. Normal immunoglobulins are polyclonal composed of a variety of heavy chains and light chains. In myeloma, plasma cells produce immunoglobulin of a single heavy and light chain, known as a monoclonal protein or paraprotein. The most well-known of these, which occurs in the urine, is known as the Bence Jones protein, which occurs when only a light chain is produced.

Diagnosis of myeloma requires two of the following criteria:

1. Increased malignant plasma cells in the bone marrow (>10%)
2. Serum or urinary paraprotein
3. A myeloma defining event (remembered by the mnemonic CRAB):
   • C – Calcium: hypercalcaemia
   • R – Renal: Renal involvement
   • A – Anaemia: low Hb
   • B – Bone: lytic bone lesions

End organ damage can occur in myeloma, with the kidneys, bone marrow or bones themselves being more susceptible. Renal failure can occur due to paraprotein deposition, hypercalcemia, an increased susceptibility to infection or amyloidosis. Treatment is often with intravenous fluids to treat the renal impairment and is the first line treatment for hypercalcemia caused by multiple myeloma.

Amyloidosis and the kidney

Overview

Amyloidosis is an acquired or inherited disorder of protein folding. Proteins which are normally soluble are deposited in the extracellular space and cause progressive organ dysfunction. The most common type of this is Amyloid A amyloidosis (AA), also referred to as secondary amyloidosis. AA amyloidosis is a rare complication of inflammatory disease and chronic infection. AL amyloidosis, also known as primary amyloidosis, is caused by the deposition of abnormal immunoglobulin light chains, which can be identified on immunohistochemistry. AL amyloidosis is commonly associated with other plasma cell diseases, e.g. myeloma or Waldenström’s macroglobulinaemia.

Amyloid is deposited in the glomerular capillaries and mesangial cells and affects the ability of the kidney to filter and excrete waste and retain plasma protein. This leads to proteinuria and nephrotic syndrome. Approximately 20% of people with AL amyloidosis will progress to needing renal replacement therapy.

Histologically, the key feature of amyloidosis on light microscopy is eosinophilic deposits, which are seen in the mesangium. Congo Red staining is positive, giving the amyloid proteins a pink colour. Under polarised light, the tissue shows an apple-green birefringence. Renal biopsy is necessary in all suspected cases of renal amyloidosis.

Treatments are targeted at reducing the production of the amyloidogenic protein and this improves kidney function. High doses of melphalan (which is a chemotherapy agent) followed by stem cell transplantation are recommended for the treatment of AL amyloidosis. In AA amyloid, management involves control of the underlying condition; biologic therapies targeted against TNF-alpha, such as infliximab and etanercept can be used.

Thrombotic microangiopathies and the kidney

Haemolytic uraemic syndrome

Haemolytic uraemic syndrome (HUS) is characterised by a thrombotic microangiopathy which causes damage to the endothelial cells of blood vessels. It causes anaemia and thrombocytopenia due to intravascular haemolysis.

The common features of HUS are:

• Anaemia
• Thrombocytopenia
• Raised unconjugated bilirubin
• Raised lactate dehydrogenase (LDH)
• Decreased circulating levels of haptoglobin
• Reticulocytosis

The microvasculature of the kidney is most affected in HUS, with the involvement of other organs only occurring in more severe cases. The most common cause of classical HUS is infection with E coli O 157 and its enterotoxin. This typically causes a diarrhoeal illness and is the most common cause of AKI in children in the developed world. This is referred to as D+HUS. The severe diarrhoea associated with HUS often leads to intravascular depletion due to dehydration and, therefore, a pre-renal acute kidney injury. There is good spontaneous recovery in most patients, but sometimes renal replacement therapy is required. In 10% of cases, no infective cause is identified, and this is called atypical HUS. Atypical HUS is subclassified into familial and sporadic subtypes and is associated with dysregulation of the complement system leading to thrombotic microangiopathy.

Thrombotic thrombocytopenic purpura

Like HUS, thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by damage to endothelial cells of small blood vessels and subsequent intravascular thrombosis. The key contrast from HUS is that the brain is more commonly involved in TTP and neurological symptoms such as reduced GCS or seizures are often present.

TTP is an autoimmune disorder caused by antibodies against ADAMTS-13, an enzyme involved in regulating platelet aggregation. This enzyme normally cleaves von Willebrand factors (vWF) and its deficiency results in large multimers which crosslink platelets.

Higher circulating levels of vWF lead to the formation of multiple thrombi as well as the depletion of platelets which in turn can cause bleeding. Red blood cells passing these microthrombi in the capillary circulation are subject to shear stress and trauma, which in turn leads to microangiopathic haemolytic anaemia and schistocyte formation. The small thrombi cause reduced blood flow and cell death; the kidney is particularly susceptible to damage as a result, due to its microcirculation and high blood flow.

TTP is characterised by a pentad of clinical features:

1. Thrombocytopenia
2. Microangiopathic haemolytic anaemia
3. Fever
4. Renal impairment
5. Neurological involvement

Untreated, mortality rates are 90% within ten days. The gold standard of treatment is emergency plasma exchange, however, corticosteroids, aspirin, and rituximab all have a role in management.

Hepatic and lung disease and the kidney

Hepatorenal syndrome

The hepatorenal syndrome (HRS) is a serious complication in patients with severe liver disease. These patients are predisposed to developing acute kidney injury in response to relatively minor insults such as bleeding or infection, and in the absence of any other identifiable renal pathology. Individuals with cirrhosis and alcoholic hepatitis are the most likely to be affected by HRS. Deterioration in liver function leads to portal hypertension and dilatation of the splanchnic circulation. This causes reduced mean arterial pressure and sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS) activation. Renal vasoconstriction and hypoperfusion, and subsequent reduced function, occurs through activation of the RAAS, stimulation of the sympathetic nervous system, and increased synthesis of vasoactive mediators. The increased salt and fluid retained through activation of the RAAS then lead to worsening of ascites. Patients with hepatorenal syndrome are often difficult to treat by dialysis and have poor prognosis.

HRS can be separated into two types:

• Type 1 is often a severe, hemodynamically mediated type of renal failure secondary to severe hepatic dysfunction and has a very poor prognosis.
• Type 2 occurs in those patients with diuretic resistant ascites.

Identifying patients most at risk and starting adequate antibiotics against spontaneous bacterial peritonitis is an important step in the prevention of HRS. Medical therapy with albumin can be effective at increasing the circulating volume, and other treatments, such as terlipressin or noradrenaline, may be used. Procedures such as transjugular intrahepatic portosystemic shunts (TIPPS) can be performed to reduce portal hypertension but HRS is usually fatal unless a liver transplant is conducted.

It is also worth noting that IgA nephropathy is more common in patients with liver disease.

Pulmonary-renal syndrome

Pulmonary-renal syndrome (PRS) is a dramatic presentation with renal and respiratory failure and has a high mortality rate. It occurs as a consequence of ANCA-positive vasculitis or of Goodpasture syndrome (also known as anti-glomerular basement membrane (anti-GBM) disease). PRS should be considered in anyone presenting with symptoms consistent with pulmonary haemorrhage and small vessel vasculitis. The way to differentiate GPA (granulomatosis with polyangiitis) from anti-GBM disease is the involvement of the upper respiratory tract, which will occur in GPA but never in anti-GBM disease.

The exact cause of anti-GBM disease is unknown but there is a predisposition in those individuals who exhibit HLA-DR15. Anti-GBM antibodies target a domain of the alpha-3 chain of type 4 collagen, which is predominantly found in the basement membranes of glomerular and alveolar capillaries, explaining the pulmonary and renal involvement of this disease. The most accurate way of achieving a diagnosis is with a renal biopsy.

PRS can also occur in pesticide poisoning with compounds such as paraquat or infection with legionella and leptospirosis. Cardiogenic shock can mimic a pulmonary renal syndrome and lead to haemoptysis due to pulmonary oedema and renal failure secondary to inadequate kidney blood flow. Treatment of PRS is predominantly with immunosuppressive medications such as steroids, cyclophosphamide, and rituximab to prevent the formation of new antibodies. In severe cases, plasmapheresis may be required to filter out the antibodies in the plasma.

HIV and the kidney

HIV associated nephropathy (HIVAN)

Renal dysfunction has been described in association with HIV infection; this can be due to HIV associated glomerulonephritis, HIV associated thrombotic microangiopathy, or secondary to antiretroviral medication nephrotoxicity.

The most common histological abnormality in HIVAN is focal segmental glomerulosclerosis or FSGS, present in over 80% of cases. Clinically, this presents with proteinuria in the nephrotic range and oedema, Hypertension and haematuria are uncommon. Over 90% of patients with HIVAN are black. If untreated, patients can go on to develop rapidly progressive chronic kidney disease. Highly active antiretroviral therapy (HAART) may result in the stabilisation of renal function and the prevention of progression to end stage renal failure.