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Renal involvement in genetic disease 

Renal involvement in genetic disease
Renal involvement in genetic disease

D Joly

and J P Grünfeld



Autosomal dominant polycystic kidney disease (ADPKD)—discussion of therapies designed to modify the disease process, e.g. somatostatin analogues, mammalian target of rapamycin (mTOR) inhibitors, vasopressin (V2) receptor antagonists.

Expanded discussion of genetic causes of familial focal segmental glomerulosclerosis and other familial primary glomerulonephritis, also of the syndrome caused by renin gene mutation.

Updated on 25 May 2011. The previous version of this content can be found here.
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There are many inherited disorders in which the kidney is affected: this chapter is concerned with the commonest inherited diseases leading to renal failure.

Autosomal dominant polycystic kidney disease—accounts for about 7% of cases of endstage renal failure in Western countries. Inheritance is autosomal dominant, with mutations in polycystin 1 responsible for 85% of cases and mutations in polycystin 2 accounting for most of the remainder, these being transmembrane proteins that are able to interact, function together as a nonselective cation channel, and also induce several distinct transduction pathways. May present with renal pain, haematuria, urinary tract infection, or hypertension, or be discovered incidentally on physical examination or abdominal imaging, or by family screening, or after routine measurement of renal function. Commonly progresses to endstage renal failure at between 40 and 60 years of age. Extrarenal manifestations include intracranial aneurysms, liver cysts, and mitral valve prolapse.

Alport’s syndrome—X-linked dominant inheritance in 85% of kindreds, with molecular defect involving the gene encoding for the α‎-5 chain of the type IV collagen molecule. Males typically present with macroscopic haematuria in childhood, followed by permanent microscopic haematuria, and later by proteinuria and renal failure. Extrarenal manifestations include perceptive deafness of variable severity, ocular abnormalities (bilateral anterior lenticonus is pathognomonic), and (uncommonly) macrothrombocytopenia. Carrier women often have slight or intermittent urinary abnormalities, but may develop mild impairment of renal function late in life, and a few develop endstage renal disease. In the autosomal recessive form of Alport’s syndrome, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women.

Nephronophthisis—the most common genetic cause of endstage renal disease in children and young adults, this is a group of autosomal recessive tubulointerstitial nephropathies with multiple small medullary cysts that appear late in the course of the disease. Eighty per cent of cases are caused by homozygous deletions of the NPH1 gene, which codes for nephrocystin. Present with polyuria, polydipsia, and growth retardation in early childhood, progressing to endstage renal disease at a mean age of 14 years.

von Hippel–Lindau disease—due to mutation in the tumour suppressor gene VHL; renal cysts and bilateral multifocal renal cell carcinomas are found in 70% of cases. Carcinomas are often asymptomatic, should be screened for regularly, and occur at a mean age of 45 years.

Tuberous sclerosis—due to mutation of genes encoding for hamartin (TSC1) or tuberin (TSC2); characterized by renal angiomyolipomas, which are benign, often multiple and bilateral.


The spectrum of inherited renal disorders (and of inherited diseases with kidney involvement) is summarized in Box 21.12.1. Attention will be focused in this section on the commonest inherited kidney diseases leading to renal failure.

Cystic kidney diseases

An overview of cystic kidney diseases is shown in Box 21.12.2.

Autosomal dominant polycystic kidney disease (ADPKD)

ADPKD is by far the most frequent inherited kidney disorder, accounting for approximately 7% of cases of endstage renal failure in Western countries. It is one of the most frequent human inherited monogenic diseases (c.1 in 1000 individuals).


The diagnosis of ADPKD is based on the two following features:

  • Evidence for autosomal dominant inheritance

  • Demonstration of multiple renal cysts in both kidneys, which are often enlarged, by ultrasonography (Fig. 21.12.1)

Fig. 21.12.1 Typical ultrasonographic findings in a patient with autosomal dominant polycystic kidney disease. The kidney is enlarged and contains multiple cysts of different sizes; the contralateral kidney had similar changes. The concentration of serum creatinine was 120 µmol/litre at the time of ultrasonography.

Fig. 21.12.1
Typical ultrasonographic findings in a patient with autosomal dominant polycystic kidney disease. The kidney is enlarged and contains multiple cysts of different sizes; the contralateral kidney had similar changes. The concentration of serum creatinine was 120 µmol/litre at the time of ultrasonography.

By courtesy of Dr O. Helenon.

The latter criterion deserves further comment. Renal cysts are initiated in the fetal kidney and develop progressively in life over the course of years. They may be too small to be detected by ultrasonography in childhood, and kidney enlargement also progresses with age. Thus, the sensitivity of ultrasonography for detecting ADPKD is poor before 20 years of age (but the specificity is high since solitary renal cysts are very rare at this age, and bilateral cysts even more so). In families with the PKD1 gene mutation, false-negative ultrasonographic diagnosis is very unlikely at ages above 30 years, and rare at ages 20 to 29 years. Routine screening of asymptomatic members of affected families should not be done before 20 years of age. By contrast, renal cysts, even bilateral, are relatively common in patients aged 50 years or more, hence strict criteria (multiple cysts in both enlarged kidneys and clear-cut inheritance) are required for diagnosing ADPKD in older patients.


Renal manifestations

In some patients, ADPKD is asymptomatic and discovered during family investigation, or by chance on abdominal ultrasonography. In most cases, however, there are symptoms and patients complain of one or more of the following at some time during their life: renal pain due to cyst development, or stone or blood clot migration; bleeding within a cyst, leading to flank pain, with the hyperdense cyst fluid then being visualized by CT; bleeding into the urinary tract, with gross haematuria occurring in approximately 30% of cases; fever due to upper urinary tract infection, which is more frequent in women, or to cyst fluid infection. Renal stones, predominantly uric acid (for unknown reasons), develop in about 20% of the patients.

Hypertension is a common and early finding in ADPKD, occurring in about 30 to 50% of patients with normal renal function. Subsequently, with the development of renal failure, up to 80% of patients become hypertensive. Why hypertension develops is not known: it has been ascribed to compression and ischaemia of the normal renal parenchyma by cysts.

Renal failure is also a common finding in ADPKD. When it occurs, it usually progresses to endstage at between 40 and 60 years of age. However, in 30% of cases it reaches endstage later, and in 5% earlier, including very rare instances when it develops in the first years of life. Recent epidemiological studies have indicated that ADPKD may have a much more indolent course in a substantial number of cases: 25 to 50% of affected subjects are not in endstage renal failure by 70 years of age, and some patients may reach 80 or 90 years without the need for renal replacement therapy. This information is crucial for genetic counselling.

Genetic and nongenetic factors determine renal prognosis: the renal disease may progress more slowly in families with PKD2 disease (mean age at endstage renal disease 55 years in PKD1 disease, compared with 70 years in PKD2 disease), it progresses more slowly in women than in men, and control of hypertension may reduce the rate of progression.

Extrarenal manifestations

Liver cysts develop in 70% of patients, usually later in life than renal cysts. They are more frequent and more diffuse in women than in men. They are usually asymptomatic but may be clinically palpable, and are typically detected by ultrasonography. Liver function tests are usually normal. Liver cyst infection may occur, particularly in patients on dialysis or in transplant recipients. Massive liver involvement can cause severe discomfort in some cases, mostly in women.

Cardiovascular abnormalities include intracranial aneurysms and mitral valve prolapse. Subarachnoid haemorrhage or intracerebral bleeding due to rupture of intracranial aneurysm are among the most severe complications of ADPKD and occur in approximately 1 to 2% of patients. Rapid diagnosis and urgent neurosurgical opinion are required. Diagnosis should be suspected early, before complete rupture, in patients with ADPKD with recent and severe headache, or with any transient focal neurological deficit.

In cross-sectional studies performed using noninvasive screening methods such as high-resolution CT or magnetic resonance angiography (MRA), intracranial aneurysms have been found in 7 to 8% of asymptomatic middle-aged patients with ADPKD. The prevalence is higher in those with a family history of intracranial aneurysm. The risk of rupture is largely dependent on aneurysm size. Routine screening by noninvasive methods is not indicated for all asymptomatic patients with ADPKD, but it seems reasonable in certain subgroups, in particular those with a family history of intracranial aneurysm or subarachnoid haemorrhage, those who have already bled from an aneurysm (since recurrent aneurysm is possible), and possibly those who are to undergo major elective surgery. In high-risk groups, screening should be repeated every 5 to 10 years since the cerebral vascular disease is progressive.

Mitral valve prolapse is discovered in 20% of patients with ADPKD by echocardiography, whereas it is found in only 2 to 3% of the general population. Other cardiac valve abnormalities and occasionally artery dissection or aneurysm may also be detected.

Other extrarenal abnormalities observed in ADPKD include pes excavatum, colonic diverticula, and abdominal hernias.


The mechanisms underlying cyst formation and progression are poorly understood: cysts develop only in a small percentage of nephrons and only focally, whereas all nephron cells carry the mutated gene. This has been explained by a two-hit phenomenon which postulates that renal tubular (or liver biliary) cells which are at the origin of cysts bear first the germinal PKD gene mutation, and then acquire a somatic PKD gene mutation involving the other allele, this event occurring at random in a limited number of cells. This explanation does not exclude other mechanisms. The link between the genetic event(s) and cystic fluid accumulation is not known.

The disease has an autosomal dominant mode of inheritance, so that the risk of any child of an affected parent carrying the abnormal gene is one in two, new mutations being very rare. Mutations affecting polycystin 1 (from the PKD1 gene on the short arm of chromosome 16) are responsible for 85% of cases, with mutations affecting polycystin 2 (from the PKD2 gene on the long arm of chromosome 4) accounting for most of the remainder. Polycystin 1 and polycystin 2 are transmembrane proteins that are able to interact, function together as a nonselective cation channel, and also induce several distinct transduction pathways. The ‘polycystin complex’ may have three different subcellular localizations and associated putative functions: at lateral membranes of the cells (with a role in cell–cell interaction); at the basal pole of the cell (with a role in cell–extracellular matrix interaction); and at the apical primary cilia of the cells (with a role in mechano-transduction of the urinary flux).

Treatment—general and symptomatic

High fluid intake and regular follow-up of blood pressure and renal function are indicated in all patients with ADPKD. The control of hypertension is an essential part of management, achieved with standard antihypertensive agents. Haematuria should be managed conservatively if at all possible, although bleeding may sometimes be prolonged over several days and even weeks.

The relief of pain or abdominal discomfort can be difficult. In addition to symptomatic treatment, surgical renal cyst decompression should be restricted to very selected cases. Surgery is rarely needed in the management of renal stones. Liver cyst aspirations by needle under CT guidance, fenestration, or resection may be needed when massive involvement gives rise to pain; and in very rare cases such patients have come to liver transplantation.

Kidney infection requires administration of antimicrobials appropriate for upper urinary tract infection (see Chapter 21.13). In some cases control of infection is not obtained, most probably because agents penetrate some infected cyst fluids poorly and do not achieve adequate concentration. Lipophilic drugs such as trimethoprim–sulphamethoxazole and ciprofloxacin have the best penetration into cyst fluid. Liver cyst infection also requires antimicrobials and drainage if infection is not controlled. Ciprofloxacin penetrates well into liver cyst fluid.

Standard medical management of chronic renal failure is indicated, as are renal replacement therapy and kidney transplantation when the patient reaches endstage, the results being similar to those obtained in other renal diseases.


Identification of polycystins and their downstream intracellular dysregulated signalling pathways has provided clues to how the disease develops and thereby to the possibility of specific interventions. Several molecules (somatostatin analogs, mTOR inhibitors, V2 receptor antagonists) have been tested and shown promise in animal models, and clinical trials are currently underway to determine their ability to reduce or reverse cystogenesis, prevent decline of renal function, and improve significant clinical outcomes. Monthly injections of octreotide (a long acting somatostatin analogue) for one year prevented increase in kidney volume but had no effect on change in GFR. Eighteen months of sirolimus treatment did not halt polycystic kidney growth; 2 years of everolimus did slow the increase in total kidney volume but did not slow the progression of renal impairment. It remains to be seen whether the benefits of any of these agents will outweigh their drawbacks: none should be used in the management of ADPKD outside the context of properly conducted clinical trials.

Genetic counselling

The pattern of inheritance of ADPKD means that the offspring of an affected subject each have a 50% risk of having the disease. The disease has a highly variable clinical course, even within a given family. Prenatal diagnosis by gene linkage studies using material derived from chorionic villus sampling has been performed and can be considered if required and if adequate family information is available, but the demand for such prenatal diagnosis has been very low in Western countries. This is explained by the late onset and the variable clinical course of the disease, often relatively benign, which cannot yet be predicted by DNA analysis.

Ultrasonography may occasionally show renal cysts in the fetus, but late in pregnancy. Obviously, due to the slow and late development of macrocysts, negative ultrasonography in the fetus (as well as in a child) does not rule out the disease.

Autosomal recessive polycystic kidney disease (ARPKD)

ARPKD is a rare inherited disease (c. 1 in 40 000 individuals), the first manifestations of which appear early in childhood. Mutations at a single locus, polycystic kidney and hepatic disease 1 (PKHD1, located on chromosome 6), are responsible for all typical forms of ARPKD. The PKDH1 gene product, fibrocystin, is a transmembrane protein localized to the cell primary cilia.

Three clinical features characterize this disease:

  • Its recessive nature: both heterozygous parents are unaffected, with normal renal ultrasonography; parental consanguinity is found in some families

  • Renal cysts derive from the collecting ducts, accounting for the striations in the dilated collecting system seen on intravenous pyelography

  • The renal disease is invariably associated with congenital hepatic fibrosis: this may be responsible for portal hypertension due to presinusoidal block, or for bacterial angiocholitis due to intrahepatic bile duct dilatation

In children, ARPKD should be differentiated from ADPKD, which can be detected in childhood, even in neonates. Family history and renal ultrasonography in parents are decisive for correct diagnosis. In very rare families with PKD1 disease, renal involvement may be revealed in neonates and may progress to endstage within the first year of life.

The diagnosis of ARPKD may be made before birth by antenatal ultrasonography, showing renal enlargement and increased echogenicity (as well as oligohydramnios). However, prenatal diagnosis may be uncertain and, since cystic changes occur in well-developed collecting ducts, these are detected only in the second half of pregnancy. When there is huge renal enlargement, pulmonary hypoplasia and respiratory distress may lead to death within hours after birth. With prolonged survival, liver and renal involvement becomes prominent. Gastrointestinal bleeding due to portal hypertension may be life threatening and necessitate surgical portocaval shunt. Systemic hypertension is a frequent finding in the first year of life but, surprisingly, it may regress in subsequent years. Urinary tract infection is common. The rate of progression of renal failure is variable: of those who survive the neonatal period, about 50% reach endstage in childhood, whilst this occurs in adulthood in the remainder.

Renal cysts and diabetes syndrome (RCAD)

Heterozygous mutations in the TCF-2 gene encoding hepatocyte nuclear factor (HNF)-1β‎, a DNA transcription factor, were initially described as one of the main molecular causes of maturity-onset diabetes of the young (MODY5). It now appears that renal anomalies are the key feature of HNF-1β‎ mutation phenotype and often precede the onset of diabetes. Renal cysts and progressive renal failure are frequent; glomerulocystic kidney disease and renal hypoplasia have been reported. Abnormal liver function tests, hyperuricaemia, hypomagnesaemia, pancreatic hypoplasia, and urogenital malformations have also been related to HNF-1β‎ mutations.

Other hereditary cystic kidney diseases

Renal cysts may be found in other autosomal dominant diseases, such as von Hippel–Lindau disease, tuberous sclerosis (see below), and HANAC syndrome (a rare condition due to COL4A1 gene mutations). Renal medullary cysts are also found in juvenile nephronophthisis, but not early in the course (see below). By contrast, such cysts—well localized in adults by ultrasonography or CT—are seen early in autosomal dominant renal medullary cystic disease. This very rare condition progresses to endstage renal failure. Three different genetic loci have so far been localized.

Inherited diseases with glomerular involvement

Alport’s syndrome

First described in 1927 by Dr Arthur Cecil Alport, this syndrome is characterized by the association of progressive haematuric hereditary nephritis and bilateral sensorineural hearing loss. Its prevalence is approximately 1 in 5000 individuals. In 85% of kindreds the mode of transmission is compatible with X-linked dominant inheritance. In the remaining families, autosomal dominant or recessive inheritance should be considered.


Renal manifestations

The first clinical manifestation is typically gross haematuria, occurring sometimes in the first year of life, recurring during childhood, and followed by permanent microscopic haematuria. Proteinuria appears later. A nephrotic syndrome, usually moderate, develops in 30 to 40% of patients. In other cases, moderate proteinuria and microscopic haematuria are the presenting symptoms in adulthood. The disease is progressive, leading to renal failure in all affected males, but the rate of progression is heterogeneous from one family to another, although usually homogeneous within a given family. In some endstage is reached at or before 30 years of age, sometimes in childhood; in others renal failure progresses to endstage between the ages of 30 and 60 years.

Carrier females of X-linked Alport’s syndrome often have slight or intermittent urinary abnormalities. They may develop mild impairment of renal function late in life, but do not usually have progressive renal disease as occurs in males, although this does happen in a few cases. In the autosomal recessive form of Alport’s syndrome, renal disease progresses to endstage before 20 to 30 years of age at a similar rate in both affected men and women.

Extrarenal manifestations

The hearing defect may lead to severe perceptive deafness, but it is often moderate or slight, only detected by audiometric testing. The hearing loss labels a given family, but is not found in all patients with renal disease. Familial haematuric progressive nephritis without hearing defect is documented in some kindreds, which forms one end of the spectrum of Alport’s syndrome.

Eye abnormalities are detected in 30 to 40% of cases. These include bilateral anterior lenticonus detected by slit-lamp examination—a pathognomonic abnormality—and perimacular or macular retinal flecks that are seen by fundoscopic examination and do not alter visual acuity. Recurrent corneal erosions occur in some patients.

In some families, macrothrombocytopenia is associated with nephritis and hearing defect. In other rare kindreds the latter features are found in association with diffuse leiomyomatosis, mainly oesophageal, and congenital cataracts.


The primary defect in Alport’s syndrome involves the glomerular basement membrane. By electron microscopy, this membrane can be abnormally thickened with splitting of the lamina densa, thinned with focal thickening, or diffusely thin in younger children. In some patients, antigenicity of the glomerular basement membrane is abnormal: antiglomerular basement membrane antibodies do not bind linearly along the Alport glomerular basement membrane, whereas they show linear fixation along the glomerular basement membranes of normal and diseased kidneys which contain the corresponding Goodpasture antigen (Goodpasture’s syndrome is an autoimmune disorder characterized by the development of antiglomerular basement membrane antibodies directed against this antigen; see Chapter 21.8.7).

In X-linked Alport’s syndrome the molecular defect involves the gene encoding for the α‎-5 chain of the type IV collagen molecule, which is a major component of basement membranes. Six α‎ chains of type IV collagen have been identified so far, with each molecule of type IV collagen being made up of three of these chains, differently associated in various basement membranes. In Alport’s syndrome, mutations have been identified in the gene encoding for the α‎-5 chain that maps to the long arm of the X chromosome. The Goodpasture antigen is located in the α‎-3 chain, the gene of which has been mapped on chromosome 2. Absence or severe alteration of the α‎-5 chain possibly prevents normal integration of the α‎-3 chain into the glomerular basement membrane, leading to the defect in antigenicity.

In the autosomal recessive form of Alport’s syndrome, the genes encoding for α‎-3 or α‎-4 chains are mutated. Affected subjects are homozygotes in consanguineous families, or compound heterozygotes in other cases. In families with leiomyomatosis, α‎-5 and α‎-6 genes, located contiguously on the X chromosome, are both involved in a large deletion.

Skin biopsy has become valuable for diagnosis of Alport’s syndrome. Epidermal basement membrane normally contains α‎-5 but not α‎-3/α‎-4 chains, hence negative α‎-5 staining by immunofluoresence is highly specific for X-linked Alport’s syndrome, but is found in only 75% of cases because α‎-5 chains that are only slightly mutated can be detected. α‎-5 Staining is normal in the autosomal recessive forms of Alport’s syndrome.

In the disease with macrothrombocytopenia, mutations involve the MYH9 gene, encoding the nonmuscle myosin heavy chain IIA.

Genetic counselling and treatment

Genetic counselling first requires the correct identification of the mode of inheritance. If X-linked dominant inheritance is documented, affected men will not transmit the disease to their sons, whereas all their daughters will carry the mutant gene; affected women will transmit the mutant gene to 50% of either sons or daughters. DNA analysis may be helpful for genetic counselling in these families.

Treatment of hypertension and supportive management of renal failure are indicated in patients with progressive disease. The results of kidney transplantation are similar to those obtained in other renal diseases, but in rare cases antiglomerular basement membrane crescentic glomerulonephritis develops in the graft. It is assumed that this complication is related to alloimmunization to the ‘missing antigen’ introduced by the transplant.

Benign familial haematuria

This disease is characterized by isolated microhaematuria, without proteinuria or progression to renal failure, in both men and women. Renal biopsy usually shows a thin glomerular basement membrane and immunofluorescence studies are negative. The mode of transmission is compatible with autosomal dominant inheritance. In some families, subjects with microhaematuria are heterozygotes carrying mutations involving the α‎-3 or α‎-4 chain gene.

Congenital nephrotic syndrome of the Finnish type

This disease specifically affects the kidney and is characterized by massive proteinuria, which occurs already in utero and then persists in infancy. Intense therapy is needed to afford the children a chance of survival: nutritional support to compensate for protein loss; prevention of infection and thrombosis; bilateral nephrectomy; continuous peritoneal dialysis, and finally kidney transplantation.

It is an autosomal recessive disease caused by mutation of the nephrin gene whose product probably has a zipper-like structure, is localized at the slit diaphragm between podocyte foot processes (which are both absent in affected subjects), and plays a key role in the normal glomerular filtration barrier.

Nail–patella syndrome

This syndrome, also known as hereditary osteo-onycho dysplasia, is a rare autosomal dominant disorder, defined by the association of nail hypoplasia or dysplasia, bone abnormalities (including iliac horns), and renal disease. The latter is found in 50 to 60% of cases, progressing to endstage in approximately 15%. The hallmark of renal involvement is the detection by electron microscopy of fibrillar collagen bundles within the glomerular basement membrane. Open-angle glaucoma is a feature in rare families.

The mutated gene, LMX1B (located on 9q), belongs to a family of transcription factors that are involved in pattern formation during development. LMX1B is more specifically involved in the dorsoventral patterning of the limbs, and mice with a deletion in their lmx1-homologue exhibit skeletal defects similar to those observed in nail–patella syndrome and abnormal dorsoventral patterning of the extremities of the limbs.

Metabolic diseases with glomerular involvement

Anderson–Fabry disease

This disease, X-linked (prevalence c.1 in 40 000 individuals) and due to α‎-galactosidase A deficiency, results in glycosphingolipid deposition, mainly in the cardiovascular and renal system. The first manifestations in hemizygotes are painful acroparaesthesias, appearing in childhood and often prevented by administration of carbamazepine or phenytoin. Angiokeratomas, anhydrosis, and corneal deposits develop subsequently. Ischaemic cerebrovascular complications, cardiac valve abnormalities, myocardial deposition of glycolipids, and coronary events are the most severe manifestations, along with renal involvement.

In the kidney, glycolipid deposition involves glomerular epithelial cells, tubular cells, and endothelial and smooth muscle cells of intrarenal arteries. The latter changes are responsible for progressive renal ischaemia. Renal disease is revealed by proteinuria at around 20 years, and then progresses to endstage between 40 and 60 years of age, necessitating regular dialysis and/or kidney transplantation. Glycolipid deposition does not recur in the renal graft that contains normal α‎-galactosidase activity.

Most heterozygote females (80%) have corneal deposits. Symptoms are usually absent or moderate because of random X-chromosomal inactivation, but they may be severe in some cases, with cardiac changes and/or symptomatic renal disease.

Diagnosis is based on symptoms, familial history, measurement of α‎ galactosidase activity in leucocytes, demonstration of typical inclusions on a tissue biopsy, and genetic analysis. Enzyme replacement therapy is available. All males with Fabry’s disease and all females with substantial disease manifestations should receive this treatment as early as possible. See Chapter 12.8 for further discussion.

Lecithin-cholesterol acyl transferase (LCAT) deficiency

This is a very rare autosomal recessive disorder. LCAT is a key enzyme in the metabolism of cholesterol, responsible for its esterification. In affected subjects the proportion of cholesteryl ester to total cholesterol is very low. Lipid accumulation occurs in the eyes (causing corneal deposits), erythrocyte membranes (leading to low-grade haemolytic anaemia), arterial walls (contributing to premature atherosclerosis), and kidneys, predominating in glomerular mesangial cells and progressing to endstage renal disease. LCAT is expressed primarily in the liver, hence liver transplantation would theoretically be the treatment of choice, but this has not so far been performed in this disease. Patients have received kidney transplants: lipid deposition recurs slowly in the graft. See Chapter 12.6 for further discussion.

Type I glycogen storage disease

Also named von Gierke’s disease (see Chapter 12.3.1), this disease is due to glucose-6-phosphatase deficiency. Affected infants develop hypoglycaemia, growth retardation, and hepatomegaly. Fanconi’s syndrome may occur as a consequence of glycogen deposition in the proximal tubule. Progressive renal involvement is not predominantly caused by glycogen accumulation, but related to the development of focal segmental glomerulosclerosis, the mechanism of which is unclear, usually after 20 years of age. This complication has only been recognized recently since children with severe hypoglycaemia have now survived to adulthood thanks to the progress achieved by paediatricians, dietitians, and families in providing adequate feeding and nutrition.

Familial focal segmental glomerulosclerosis and other familial primary glomerulonephritis

Familial focal segmental glomerulosclerosis with either autosomal dominant or autosomal recessive inheritance has recently been well characterized. Mutation of the NPHS2 gene, which encodes podocin, and mutations of PLCe, may cause recessive steroid-resistant nephrotic syndrome in some families, which can be of early or late onset. Mutations in ACTN4, which encodes α‎-actinin-4, mutations of TRPC6 and mutations of INF-2 (which encodes formin) may cause autosomal dominant focal segmental glomerulosclerosis. All these proteins are synthesized and secreted by the podocytes, and interact and regulate plasticity and slit diaphragm permselectivity with other podocyte proteins. Mutations (especially podocin mutations) may be detected in some cases of sporadic steroid-resistant nephrotic syndrome.

For most types of other primary glomerulonephritis, familial cases have been anecdotally reported. The most frequent form, albeit rare, is probably familial IgA nephropathy, either primary (Berger’s disease) or associated with Henoch–Schönlein purpura.

Inherited tubulointerstitial disorders

Juvenile nephronophthisis

Nephronophthisis is a group of autosomal recessive tubulointerstitial nephropathies with multiple small medullary cysts that appear late in the course of the disease. It is the most common genetic cause of endstage renal disease in children and young adults. Many patients have no obvious family history. Eighty per cent of cases are caused by homozygous deletions of the NPH1 gene, which codes for nephrocystin. At least three other genes (NPH2, 3, and 4) account for the remainder of the cases, and the respective encoded proteins (inversin, nephrocystin 3, nephrocystin 4) may interact in common signalling pathways downstream of primary cilia.

Polyuria, polydipsia, growth retardation, and urinary sodium leak are usually present before 4 years of age. Proteinuria is a late finding. Renal failure appears before 12 years of age in most cases and uniformly progresses to endstage renal disease before 20, with a mean age of 14 years. On ultrasound examination the kidneys have a normal or slightly reduced size with smooth outline, increased echogenicity, and loss of corticomedullary differentiation. Multiple small or large cysts at the corticomedullary junction are usually seen in advanced renal failure. Histology reveals atrophic tubules alternating with groups of dilated or collapsed tubules, and homogeneous or multilayered thickening of basement membranes is highly suggestive of nephronophthisis.

In about 10 to 15% of cases renal involvement is associated with retinal changes comprising tapetoretinal degeneration with or without retinitis pigmentosa, leading to blindness early or later in life (this association is referred to as the Senior–Loken syndrome, in most cases of which no deletion of the NPH1 gene has been detected). Mental retardation, cerebellar ataxia, various bone anomalies, and hepatic fibrosis have been described in some families.

Detection of NPH1 homozygous deletions allows diagnosis for the propositus and siblings without the need for renal biopsy, also prenatal diagnosis.

Uromodulin and renin mutations

Hereditary mutations of UMOD, which codes for uromodulin (or Tamm–Horsfall protein), the most abundant protein in normal urine, lead to an autosomal dominant renal disease characterized by juvenile onset of gout; hyperuricaemia disproportionate to the age, sex, or degree of renal dysfunction, which is due to low renal fractional excretion of urate; corticomedullary cysts; and renal failure often recognized between 20 and 40 years of age. Renal biopsy shows nonspecific tubulointerstitial changes. This entity was previously called ‘familial juvenile hyperuricaemic nephropathy’ or ‘medullary cystic kidney disease type 2’. Allopurinol is indicated to prevent gout, and perhaps to slow the progression of renal disease. A similar clinical syndrome causing the autosomal dominant inheritance of chronic kidney disease, hyperuricaemia, and anaemia has recently been attributed to mutations in the REN gene encoding renin.

Genetic disorders with nephrolithiasis

Pertinent clinical data on these disorders are summarized in Table 21.12.1. Additional information can be found in Chapters 21.14, 21.15, and 21.16.

Table 21.12.1 The main inherited disorders associated with nephrolithiasis


Mode of transmission

Type of stone

Chronic renal failure

Specific treatment





  • Urine alkalinisation

  • D-penicillamine or other chelators

Idiopathic hypercalciuria




Diet (normal sodium and protein intake) Thiazide

Primary hyperoxaluria type I


Monohydrated calcium

Yes (nephrocalcinosis)

Vitamin B6


Liver transplantation

Dent’s disease



Yes (nephrocalcinosis)

Distal tubular acidosis




Potassium citrate or bicarbonate

HPRT deficiency (Lesch–Nyhan syndrome)


Uric acid


  • Urine alkalinisation

  • Allopurinol

APRT deficiency



Yes (rarely)






AD, autosomal dominant; APRT, adenine phosphoribosyl transferase; AR, autosomal recessive; HPRT, hypoxanthine-guanine phosphoribosyl transferase; XR, X-linked.

Other genetic diseases with kidney involvement


Two diseases of this group have significant renal involvement: von Hippel–Lindau disease and tuberous sclerosis.

In von Hippel–Lindau disease, renal cysts and bilateral multifocal renal cell carcinomas are found in 70% of the patients. Carcinomas are often asymptomatic, should be screened for regularly (Fig. 21.12.2), and occur at a mean age of 45 years. Nephron-sparing surgery (tumorectomy) or percutaneous radiological interventions (radiofrequency ablation or cryoablation) are advocated when technically feasible.

Fig. 21.12.2 CT of the kidneys in a patient with von Hippel–Lindau disease. In the right kidney, a solid tumour is found as well as cystic changes. In the left kidney, a voluminous multilocular tumour is detected with thick walls, corresponding to renal clear cell carcinoma, associated with other cystic lesions.

Fig. 21.12.2
CT of the kidneys in a patient with von Hippel–Lindau disease. In the right kidney, a solid tumour is found as well as cystic changes. In the left kidney, a voluminous multilocular tumour is detected with thick walls, corresponding to renal clear cell carcinoma, associated with other cystic lesions.

The most typical renal lesion encountered in tuberous sclerosis is angiomyolipoma, which is a benign tumour, often multiple and bilateral. By ultrasonography this tumour is hyperechogenic, and by CT it is characterized by its fat content (Fig. 21.12.3). Bleeding is the main complication of renal angiomyolipoma, although multiple angiomyolipomas may rarely severely reduce renal mass and lead to renal failure. The development of segmental glomerulosclerosis may accelerate the progression to endstage. Renal cysts may also be found in TSC2 forms (see below), and the incidence of renal cell carcinoma is slightly higher than in the general population.

Fig. 21.12.3 Multiple bilateral renal angiomyolipomas in a patient with tuberous sclerosis (CT scan). Note the voluminous angiomyolipoma (with high content of fat that is black) at the periphery of the right kidney.

Fig. 21.12.3
Multiple bilateral renal angiomyolipomas in a patient with tuberous sclerosis (CT scan). Note the voluminous angiomyolipoma (with high content of fat that is black) at the periphery of the right kidney.

The genes mutated in von Hippel–Lindau disease and tuberous sclerosis are tumour-suppressor genes. Two mutations (‘two-hit’ phenomenon) are required to trigger tumour formation: the first one is germinal, inherited, and the second one is somatic. The VHL gene has been cloned and located on 3p. Two somatic mutations of the same gene are involved in sporadic renal cell carcinoma. Two genes are identified in tuberous sclerosis: TSC1 on chromosome 9q, encoding for hamartin, and TSC2 on chromosome 16p, encoding for tuberin.


Cystinosis (which is completely different from cystinuria that is due to defective reabsorption of cystine in the proximal tubule, see Chapter 21.14) results from defective carrier-mediated transport of cystine through the lysosomal membrane. The disease is transmitted as an autosomal recessive trait with an incidence of about 1 in 200 000 live-born babies and is due to mutations in the gene encoding cystinosine. The diagnosis is based on the findings of cystine crystals in tissues, such as the eyes, and on the elevated cystine content in leucocytes.

The clinical manifestations are due to progressive intralysosomal accumulation of cystine. In the infantile form, the first symptoms are related to the clinical consequences of Fanconi’s syndrome (salt and water depletion, hypokalaemia, acidosis, rickets) appearing before 6 months of age. Renal failure develops later, reaching endstage generally before 12 years. Cystine accumulates in other tissues, both before and after kidney transplantation: eyes (photophobia due to corneal deposits, then retinal depigmentation and visual impairment), thyroid gland (hypothyroidism), liver and spleen (portal hypertension), pancreas (diabetes mellitus), muscles, testis, and central nervous system (encephalopathy) (see Chapter 12.2).

In addition to symptomatic management, cysteamine has proved to be effective in cystinosis. It accumulates within lysosomes, promotes cystine outflow, and thus reduces tissue cystine content. Administration of this drug should be started as soon as the diagnosis is made. It may slow the rate of progression of renal failure and prevent most extrarenal complications. However, despite recent progress, tolerance of the drug is not good because of its offensive taste and odour, so compliance may be poor. Topical cysteamine prevents corneal crystal deposition.

Juvenile cystinosis is very rare, but can present in late childhood or early adult life with renal involvement.

Malformation syndromes with kidney involvement

The most frequent of these rare syndromes is Bardet–Biedl syndrome. This is a heterogeneous autosomal recessive condition for which six different genetic loci have been identified. Clinical features comprise obesity, hypogonadism (in males), polydactyly or dystrophic extremities, retinal dystrophy (leading to blindness), and renal abnormalities. The last have only been recognized recently as a cardinal feature in the syndrome. Renal imaging often shows the following abnormalities: calyceal clubbing and pronounced diverticula, and lobulated renal outlines of the fetal type. These changes are probably dysplastic in nature, and are characteristic when associated. Renal cortical and medullary cysts have also been found by ultrasonography, but the latter may be difficult to differentiate from calyceal diverticula. Approximately 25% of patients develop chronic renal failure, progressing to endstage, which is probably the major cause of death. The most important treatment is the provision of specialized education with low-vision aids. Symptomatic management of diabetes mellitus (found in 30%), hypertension, and renal failure is required.

Renal hypoplasia or unilateral renal agenesis is found in other malformation syndromes, such as the following.

  • Kallmann’s syndrome—with hypogonadism and hyposmia or anosmia; caused by mutation of the fibroblast growth factor-1 gene (or others).

  • Branchio-oto-renal syndrome—where laterocervical fistulas or cysts and otic abnormalities, involving the outer, middle, or inner ear are found, and the EYA1 gene, on the long arm of chromosome 8, is mutated. This gene is the homologue of a gene present in drosophila, the mutation of which leads to eye absence.

  • Renal–coloboma syndrome—with optic nerve coloboma and sometimes hearing defect, and where the PAX2 gene, located on 10q, is mutated.

  • Alagille’s syndrome—characterized by paucity of intrahepatic bile ducts leading to cholestasis, vertebral abnormalities (butterfly vertebra), and heart defects; caused by mutations of JAG1 or NOTCH2 genes.

All these genes implicated in malformation syndromes are involved normally in the control of kidney development.

Further reading

Cystic kidney diseases

Hildebrandt F. (2010). Genetic kidney diseases. Lancet, 375, 1287–95.Find this resource:

Hogan MC et al. (2010). Randomised clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol, 21, 1052–61Find this resource:

Pirson Y, Chauveau D (1996). Intracranial aneurysms in ADPKD. In: Watson ML, Torres VE (eds) Polycystic kidney disease, pp. 530–47. Oxford University Press, Oxford.Find this resource:

    Pirson Y, Chauveau D, Grünfeld JP (1998). Autosomal-dominant polycystic kidney disease. In: Davison AM, et al. (eds) Oxford textbook of clinical nephrology, pp. 2393–415. Oxford University Press, Oxford.Find this resource:

      Serra AL et al. (2010). Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N Engl J Med, 363, 820–9.Find this resource:

      Torres VE. (2010) Treatment strategies and clinical trial design in ADPKD. Adv Chronic Kidney Dis, 17: 190–204.Find this resource:

      Walz G et al. (2010). Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med, 363, 830–40.Find this resource:

      Wilson PD, (2004). Polycystic kidney disease. N Engl J Med, 350, 151–64.Find this resource:

      Alport’s syndrome

      Flinter FA, et al. (1988). Genetics of classic Alport’s syndrome. Lancet, ii, 1005–7.Find this resource:

        Grünfeld JP, Knebelmann B (1998). Alport’s syndrome. In: Davison AM, et al. (eds) Oxford textbook of clinical nephrology, pp. 2427–37. Oxford University Press, Oxford.Find this resource:

          Kashtan CE (2004). Familial hematuria due to type IV collagen mutations: Alport syndrome and thin basement membrane nephropathy. Curr Opin Pediatr, 16, 177–81.Find this resource:

          Inherited diseases with glomerular involvement

          Eng CM, et al. (2006). Fabry disease. Genet Med, 8, 539–48.Find this resource:

          Lonser RR (2003). von Hippel-Lindau disease. Lancet, 351, 2059–67.Find this resource:

          Morgan SH, Grünfeld JP (1998). Inherited disorders of the kidney. Oxford University Press, Oxford.Find this resource:

            Yates JRW (2006). Tuberous sclerosis. Eur J Hum Genet, 14, 1065–73.Find this resource:

            Inherited tubulointestinal disorders

            Bleyer AJ, Zivna M, Kmoch S. (2011). Uromodulin-associated kidney disease. Nephron Clin Pract, 118, 31–6.Find this resource:

            Cameron JS et al. (1998). Inherited disorders of purine metabolism and transport. In: Davison AM, et al. (eds) Oxford textbook of clinical nephrology, pp. 2469–84. Oxford University Press, Oxford.Find this resource:

              Hildebrandt F, Jungers P, Grünfeld JP (2001). Medullary cystic and medullary sponge renal disorders. In: Schrier RW (ed.) Diseases of the kidney, pp. 521–46. Little Brown, Boston.Find this resource:

                Genetic diseases with kidney involvement

                Parfrey PS (1998). Bardet–Biedl syndrome. In: Morgan SH, Grünfeld JP (eds) Inherited disorders of the kidney, pp. 321–39. Oxford University Press, Oxford.Find this resource: