Renal Manifestations of Systemic Disease

See also:
Acute renal failure,
Chronic renal failure,
Interstitial nephritides and nephrotoxins,
Hepatorenal syndrome,
Management of individuals with chronic kidney disease,
Drug prescribing in renal impairment.

A huge variety of systemic conditions can affect the function of the kidneys. Any acute illness that causes prolonged hypotension is likely to cause renal hypoperfusion and, at least temporarily, renal impairment. Other illnesses, or toxic effects of the drugs used to treat them, can cause insidious renal dysfunction. This article cannot cover all possible causes of renal disease, but gives an overview of the potential renal consequences of some of the commoner/more important systemic diseases. Follow links to obtain more information on the relevant disease entities, or on the specifics of management of renal disease.

This is the commonest cause of endstage renal failure (ESRF) in the developed world, accounting for about 30–40 % of cases of ESRF. It's incidence is rising in line with that of diabetes in the population. It is defined as the following clinical syndrome in a diabetic patient:

• It is more common as a complication of type 1 diabetes mellitus, although it can affect a significant proportion of type 2 patients.³
• It usually affects patients who have had diabetes for >10 years, with peak incidence of ~3% per year in those who have had diabetes for 10–20 years.²
• Patients with albumin secretion of 30–300 mg/day are said to have incipient nephropathy or microalbuminuria (further defined as albumin excretion >20 μg/min).
• Microalbuminuria can be prevented from progressing to frank diabetic nephropathy by careful management.
• Without treatment incipient nephropathy usually progresses.
• The benefits of treatment in cases of established nephropathy are less clear but treatment leads to reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease.³
• Diabetic nephropathy significantly increases the risk of micro and macrovascular complications of diabetes.

Renal disease can cause hypertension, but sustained hypertension damages the vasculature of the kidneys. This is particularly so in cases of accelerated or malignant hypertension. Hypertensive nephropathy accounts for about a quarter of all patients with ESRF.⁴ Hypertension causes a pathology known as nephrosclerosis due to ischaemia affecting the glomeruli, and hyperfiltration causing intraglomerular hypertension.

Hypertension also increases the risk of renal failure through the effects of:

• Cholesterol embolisation to the kidneys
• The presence of renal artery stenosis (particularly if bilateral)

Most patients present with significant hypertension and/or its complications (e.g. cardiac failure, MI, stroke) or biochemical/clinical evidence of renal failure. There has usually been a history of hypertension for about 10 years, but some patients will present without having had any previous evidence of hypertension.

• Management is through use of a range of anti-hypertensive agents, particularly ACE inhibitors/angiotensin-2 antagonists and diuretics, but other agents are also used.
• The cohort of patients with hypertensive nephropathy are at risk of bilateral renal artery stenosis which may preclude the use of ACE inhibitors due to worsening of renal function.
• Renal parameters must be monitored very closely after introduction/dose-alteration of an anti-hypertensive agent.
• Close attention to modification of other cardiovascular risk factors and renal replacement therapy are also useful in improving long-term outlook.
• Revascularisation of the kidneys (via angioplasty/stenting) may be considered in cases of bilateral renal artery stenosis where there is evidence from captopril renography that it is significantly affecting renal function.
• It is currently unclear whether medical or instrumental revascularisation therapies give the best prognosis, but a current trial (CORAL – Cardiovascular Outcomes in Renal Atherosclerotic Lesions) is attempting to answer this question.⁵

Primary systemic vasculitides may cause renal dysfunction through their ability to cause a focal necrotising glomerulonephritis. They usually cause a pattern of renal disease known as rapidly progressive glomerulonephritis (RPGN).⁶ Vasculitides that affect the renal vasculature tend to be those that affect medium-sized arteries.

• A form of microscopic polyangiitis that affects only the kidneys occurs and is known as renal-limited necrotizing crescentic glomerulonephritis.
• These conditions are usually (80–90% of cases) associated with the presence of ANCA-positive autoantibodies.
• ANCA stands for anti-neutrophil-cytoplasmic antibody.
• It is thought that neutrophils and mononuclear phagocyte cells are activated by the presence of ANCA and these cells launch an inflammatory attack on blood vessel walls causing injury to the renal vasculature, similar to the other causes of RPGN (antibodies directed against the glomerular basement membrane or immune-complex mediated damage).
• There is a rapid impairment in renal function with GFR falling by about 50% or so in a period of days to 2–3 months.
• Histology of affected renal tissue shows marked fibrinoid necrosis with extensive crescent formation in at least half of all glomeruli.
• Clinically often presents as flu-like illness with malaise, myalgia, fever, arthralgia, anorexia and weight loss.
• Symptoms of renal impairment may then become evident along with other vasculitic symptoms such as abdominal pain, painful skin nodules/ulceration or migratory polyarthralgia.
• If the upper airways are involved there may be haemoptysis, sinusitis, cough and/or dyspnoea.
• Management is by systemic immunosuppression, usually using a combination of high-dose corticosteroid and cyclophosphamide.
• Azathioprine may be used in place of cyclophosphamide.
• Renal replacement therapy and plasmapheresis are utilised in the acute phase of the illness.

• The kidneys are often affected by the systemic autoimmune process of SLE.
• This is termed lupus nephritis; there are many patterns and classifications of disease and some may resemble glomerulonephritis.
• It is thought that nearly all patients with SLE will have histological evidence of renal involvement, even if it is not causing clinical problems.⁷
• As therapies for SLE improve, so the prevalence of life-threatening renal disease associated with the condition is falling.
• It is thought that the condition causes the formation of immune complexes that are deposited in the glomerular basement membrane leading to activation of the complement cascade and an influx of active inflammatory cells.
• Around 50% of patients with SLE are affected by lupus nephritis, with 10–20% having evidence of lupus nephritis at presentation.⁷
• Renal impairment may be detected by routine U&E testing in SLE patients, or by the detection of proteinuria which can often be severe enough to cause nephrotic syndrome.
• Haematuria may be detected by urinalysis, or microscopy which may also detect glomerular casts.
• Renal biopsy is usually needed to confirm the diagnosis.
• Management is through the use of systemic immunosuppression with steroids ± cyclophosphamide, azathioprine or mycophenolate mofetil.
• Hypertension needs to be rigorously controlled, using ACE inhibitors usually if they are tolerated in terms of renal function.
• Renal replacement therapy may be needed in severe cases and transplantation may be necessary for end-stage disease, although results are poorer than for non-SLE patients.

• Progressive systemic sclerosis, also known as scleroderma, may affect the kidneys through the presence of a microangiopathy which may cause a chronic renal impairment, or via the precipitation of a renal crisis.
• Renal crisis tends to affect those patients with diffuse, sudden onset dermatological involvement (the form affecting about a quarter of patients who have systemic sclerosis).
• Renal crisis affects about 10% of patients with systemic sclerosis.
• Renal crisis causes accelerated hypertension, oliguric renal impairment, headache, peripheral oedema and fatigue; there is a precipitate rise in urea/creatinine.
• It tends to occur within the first four years or so of diagnosis (about 75% of cases of renal crisis) but can occur at any time in the course of systemic sclerosis.
• There is a small subset of cases (~10%) that occur without the presence of hypertension.
• The condition can be ameliorated and prevented from progressing to acute renal failure by careful monitoring for its onset, and urgent commencement of treatment with ACE inhibitors.⁹
• Despite the availability of this therapy, up to 50% of sufferers will progress to acute renal failure.⁹
• Once established the condition must be treated with renal replacement therapy; some patients will become permanently dependent on dialysis, others may need it temporarily, and remission may occur up to 18 months after starting dialysis.

• This autoimmune sicca syndrome occurs in association with a range of other autoimmune conditions and can cause renal disease via glomerulonephritis (mesangial proliferative type), interstitial nephritis or renal tubular acidosis.¹⁰
• Renal disease affects about 5% of those who suffer Sjögren's syndrome.¹¹
• Typical presenting features for interstitial nephritis include polyuria and renal calculi; it tends to be an early feature of the primary condition.
• Glomerulonephritis is a late feature of the syndrome and appears to carry a relatively poor prognosis.¹⁰

Renal failure is a common finding in cases of multiple myeloma, affecting up to about 20% of cases at presentation and up to 50% through the course of the disease. There are a range of factors that predispose myeloma patients to renal impairment.

• The presence of renal failure can affect the patient's ability to tolerate chemotherapy, but most patients suitable for treatment can tolerate a modified dosing regimen of melphalan and autologous stem-cell transplantation.¹²
• Dependence on dialysis is relatively common and some cases are treated by plasma exchange in the acute phase.
• If myeloma enters complete remission then patients can be considered for renal transplantation.¹³

• In this condition, patients with cryoglobulinaemia-associated vasculitis appear to be most susceptible to renal disease, particularly if their condition is associated with Hepatitis C infection.
• Renal pathology may be caused by thrombosis or immune complex deposition leading to membranoproliferative glomerulonephritis.¹⁴
• Renal impairment tends to present as isolated proteinuria or haematuria, rather than nephrotic syndrome, nephritic syndrome or acute renal failure.¹⁴
• It usually manifests early in the course of cryoglobulinaemia (within first 5 years).
• Renal disease is an indication to aggressively treat cryoglobulinaemia as failure to do so can mean that renal failure is the end result.
• Treatment is through systemic immunosuppression using corticosteroids ± azathioprine/cyclophosphamide.
• Plasmapheresis is used to treat acute complications related to intravascular cryoprecipitation.
• Interferon-alfa is used, particularly in HCV-associated cases, to decrease the risk of severe complications, including renal failure, associated with the condition.

• This is predominantly a disease of children and causes a triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure.
• It is the most common cause of acute renal failure in children and is usually precipitated by an acute infective gastroenteritis (usually E. Coli, Shigella, Salmonella, Yersinia or Campylobacter spp.) or upper respiratory tract infection.¹⁵
• The illness starts with symptoms of the precipitating infection and there may be significant gastrointestinal blood loss with widespread petechiae.
• It is treated with supportive care, dialysis as renal replacement therapy and plasma exchange in severe cases.
• Approximately 85% of sufferers make a full recovery, but a small proportion go on to suffer chronic renal failure.

• Many children with sickle cell disease develop hyposthenuria, an inability to form concentrated urine, that may cause nocturnal enuresis and polyuria.
• Acute severe haematuria may occur due to renal papillary necrosis or sickling within the substance of the kidney and is usually treated with ddAVP/epsilon-aminocaproic acid.
• A post-mortem series of adult patients with sickle cell disease found that renal failure was the cause of death in about 20% of cases.¹⁶
• The disease causes a glomerulopathy with proteinuria and progressive renal insufficiency, leading to ESRF; renal papillary necrosis is another possible mechanism of acute renal syndromes.
• Albuminuria is a sensitive marker of glomerular damage and precedes the onset of renal failure.¹⁷
• There are no effective therapies to prevent the onset of renal failure other than good management of the condition in order to reduce the incidence of, and ameliorate, sickling crises.
• Great care should be taken to avoid or adjust the dose of nephrotoxic drugs which may precipitate acute or acute on chronic renal impairment.
• Those with ESRF will require renal replacement therapy and should be considered for transplantation.