DiagnosisClinical Diagnosis Familial juvenile hyperuricemic nephropathy type 2 (FJHN2) is defined by the presence of a mutation in REN, the gene encoding renin [Zivná et al 2009, Bleyer et al 2010a, Moriniere et al 2010]. FJHN2 is also known as REN-associated kidney disease.Clinical findings include the following:Hypoproliferative anemia with low hemoglobin concentrations found in most affected children by age one year as a result of low erythropoietin productionHyperuricemia and gout found in most (not all) affected individuals as a result of decreased renal excretion of uric acid Slowly progressive chronic tubulo-interstitial kidney diseaseAutosomal dominant inheritanceFewer than ten families have been identified with FJHN2 to date; therefore, the spectrum of clinical manifestations may not yet be fully appreciated.TestingAnemia. Hemoglobin concentrations can be low (usually 9 - 11 g/dL) as early as the first year of life. Hemoglobin concentrations remain low until adolescence, when the hemoglobin concentration increases to the normal range (if renal failure is not severe). The hemoglobin concentrations decrease again when chronic kidney disease develops. Zivná et al [2009] found that the anemia is hypoproliferative: Reticulocyte count: low relative to the hemoglobin concentration Erythropoietin concentration: low The red blood cell count responds rapidly to treatment with low-dose erythropoietin (see Management).All other hematologic aspects are normal:Mean corpuscular volumeIron stores. Note: Individuals with depleted iron stores at the time of initial evaluation remain anemic after iron is replenished.Bone aspirate (from one individual) White cells and platelets: normal in quantity, morphology, and functionSerum concentration of uric acid. Hyperuricemia (serum uric acid concentration >6 mg/dL) is present in 80% of affected individuals beginning in childhood. Usually, hyperuricemia in an individual with normal kidney function corresponds to a serum concentration of uric acid greater than one standard deviation of the normal value for age and sex. Note: It is important to compare the serum uric acid concentration with age- and gender-specific normal values (see Table 1) [Wilcox et al 1996].Table 1. Serum Uric Acid Concentration in Individuals with Normal Renal FunctionView in own windowAgeSerum Concentration (mg/dL)MalesFemales<5 years3.6±0.93.6±0.95-10 years4.1±1.04.1±1.012 years4.4±1.14.5±0.915 years5.6±1.14.5±0.9>18 years6.2±0.84.0±0.7Mikkelsen et al [1965], Harkness & Nicol [1969], Wilcox [1996] Fractional excretion of urinary uric acid is decreased in the vast majority of individuals with FJHN2.The fractional excretion of urinary uric acid can be calculated as shown: View in own windowUrine uric acid concentration x serum creatinine concentration ÷ serum uric acid concentration x urine creatinine concentrationIn affected individuals, the fractional excretion of uric acid is usually lower than 5% in adult men and lower than 6% in adult women. The reduction of urate excretion is an early event since it can be detected in affected children who have preserved renal function. Note: (1) The fractional excretion of urinary uric acid can be measured from a spot urine sample; however, a 24-hour urine collection is preferable. (2) Aspirin, diuretics, and nonsteroidal agents should be avoided during the collection. (3) Because the fractional excretion of uric acid rises above 5% as renal function worsens, this test is not sensitive in individuals with FJHN2 who have an estimated glomerular filtration rate less than 70 mL/min. (4) Because of limited experience in children younger than age three years, the level of fractional excretion of urate is not known; it is likely to be low.Table 2 provides the reference ranges by age in individuals with normal kidney function. A fractional excretion of urate more than 1 SD below the mean suggests reduced urate excretion. Table 2. Fractional Excretion of Urinary Uric Acid in Individuals with Normal Renal FunctionView in own windowAgeMeanStandard Deviation0-6 weeks29.1%11.76 weeks - 1 year23.9%10.41-3 years15.2%6.23-13 years12.2%5.5>13 yearsFemale8.0%3.7Male10.3%4.2Stiburkova [2006]Kidney function and findingsUrinalysis reveals bland urinary sediment (i.e., little blood or protein). Usually hematuria is not present, and excretion of protein is less than 1 g/24 hours except when kidney failure is advanced. Plasma renin activity is usually low but not entirely suppressed. With sodium restriction, affected individuals may have plasma renin activity in the low-normal range. Plasma renin activity is responsive to hydration status in both healthy individuals and individuals with FJHN2. For example, a normal control who is well hydrated may have a low plasma renin activity. A person with FJHN2 who is dehydrated may have a plasma renin activity in the low-normal range. For this reason, plasma renin activity must be interpreted based on hydration status and thus is not useful in establishing a diagnosis in this condition. Plasma aldosterone concentration is low but not entirely suppressed, and, as with plasma renin activity, is a function of hydration status; thus it cannot be used to establish a diagnosis in this condition. Renal ultrasound examination reveals normal or small kidney size, with no evidence of cyst formation. Kidney biopsyHistologic examination reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis [Zivná et al 2009]. Because biopsy findings are nonspecific, kidney biopsy should not be used routinely in the diagnosis of FJHN2. Immunostaining for renin and prorenin is markedly decreased compared to control tissues in the granular cells of the juxtaglomerular apparatus and undetectable in the tubular epithelium early in the course of the disease. In advanced stages, neither the granular cells of the juxtaglomerular apparatus or the tubular epithelium stain for renin or prorenin.
In all individuals with a REN mutation who were examined, abnormal localization of renin and prorenin inside the walls of several arterioles and small arteries was found [Zivná et al 2009, Bleyer et al 2010a]. Molecular Genetic Testing Gene. REN, encoding renin, is the only gene in which mutations are known to cause familial juvenile hyperuricemic nephropathy type 2 (FJHN2). Clinical testingSequence analysis. To date only four families with this phenotype and a REN mutation have been identified; therefore, mutation detection frequency is unknown [Zivná et al 2009, Bleyer et al 2010a]. In these families only REN missense mutations or small in-frame deletions affecting the signal sequence of preprorenin were observed. Table 3. Summary of Molecular Genetic Testing Used in Familial Juvenile Hyperuricemic Nephropathy Type 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityRENSequence analysisMissense mutations or small in-frame deletions4/4 families 2Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Zivná et al [2009], Bleyer et al [2010a] Interpretation of test resultsMutations localized within the signal sequence and/or potentially affecting renin glycosylation and trafficking are highly suggestive for FJHN2. Mutations in the C-terminal part of the protein may be benign [Villard et al 1994; Bleyer and Kmoch, unpublished data]. If there is a question whether the mutation is causative, other family members (affected and unaffected) should be sequenced to help determine the significance of the mutation. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a proband (see Figure 1)FigureFigure 1. Testing strategy for inherited kidney disease 1.Urinalysis to evaluate for presence or absence of hematuria or proteinuria. If the urinary sediment is bland (little proteinuria and no hematuria), the individual has a form of inherited interstitial kidney disease. (If blood or protein is present in the urine, consider inherited glomerulonephritis such as Alport syndrome.) 2.Renal ultrasound examination to evaluate for the presence or absence of cysts. (Presence of multiple cysts suggests autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease.)3.Family history to determine if the kidney disease is inherited in an autosomal dominant manner. If the disease is inherited in an autosomal recessive manner other conditions, such as nephronophthisis, should be considered (see Differential Diagnosis).4.Consider molecular genetic testing of UMOD (encoding uromodulin) or REN in individuals with autosomal dominant inheritance of progressive chronic kidney disease with inactive urinary sediment. Testing may be considered sequentially or simultaneously.
Note: (1) Mutations in UMOD are more common than mutations in REN. See UMOD-Related Kidney Disease. (2) Consider molecular genetic testing of UMOD first if there is a strong family history of gout and no history of childhood anemia. (3) Consider molecular genetic testing of REN first if there is a family history of anemia in childhood, mild hyperkalemia, and mild hypotension. 5.Consider referral to a center studying inherited kidney disease if no mutation is identified in either REN or UMOD. Note: Kidney biopsy should NOT be performed to establish a diagnosis of REN-associated kidney disease because it is an invasive procedure with some risk and pathologic findings are too nonspecific to reliably identify the causative disorder. Molecular genetic testing, the gold standard for diagnosis, is safer and less expensive than kidney biopsy. However, some affected individuals (or their relatives) may have undergone kidney biopsy prior to consideration of REN-associated kidney disease as a diagnostic possibility.Predictive testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with heterozygous mutations in REN.Homozygosity or compound heterozygosity for a null REN mutation results in grossly normal kidneys that show loss of proximal tubular differentiation. Autosomal recessive renal tubular dysgenesis is lethal in the perinatal period [Gribouval et al 2005].}

Natural History Children with familial juvenile hyperuricemic nephropathy 2 (FJHN2) may first be identified at age one year when a low hemoglobin concentration is identified during routine well child care. Although the children are asymptomatic, mild kidney failure may be evident on tests of renal function at that time. Affected, but as yet undiagnosed children placed on a nonsteroidal anti-inflammatory drug (NSAID) during a febrile illness may develop acute kidney failure due to the combination of low plasma renin activity, volume depletion, and prostaglandin inhibition [Bleyer et al 2010a]. Acute kidney failure usually resolves if treated appropriately, but chronic kidney failure and anemia may first be noted at that time. Hyperuricemia with a low fractional excretion of uric acid is present in childhood but is usually asymptomatic. As the child enters adolescence, the anemia resolves, and the hemoglobin concentration falls within the normal range. Elevated uric acid concentrations may result in gout. Gout that is treated with allopurinol is easily controlled; however, if not treated, gout may become a persistent, chronic problem. Some, but not all, affected individuals have:Decreased urinary concentrating ability resulting in excessive urine output and polyuria [Bleyer et al 2010a]. Polyuria present in childhood persists into adulthood.Mildly low blood pressure and a mildly elevated serum potassium concentration Over time, renal function slowly worsens. A mildly elevated serum creatinine concentration and reduced estimated glomerular filtration rate in an asymptomatic child often progresses to end-stage renal disease (ESRD) in the fourth to sixth decades of life. Renal replacement therapy may be necessary in the fourth through seventh decades of life. Kidney transplantation cures the condition.It is important to note that because fewer than 20 persons with this condition have been clinically characterized, more variation in clinical presentation may be found as more becomes known about the disease.

Differential DiagnosisChronic tubulo-interstitial kidney diseasePolycystic kidney disease. In persons with kidney disease inherited in an autosomal dominant manner, one must first exclude autosomal dominant polycystic kidney disease (ADPKD), in which a large number of cysts are seen on renal ultrasound examination in affected individuals older than age 25 years.If the urinary sediment is bland (i.e., with little blood or protein) and the individual does not have ADPKD, the two other forms of autosomal dominant tubulo-interstitial kidney disease to consider are: Medullary cystic kidney disease type 1 (MCKD1), linked to chromosome 1q21 [Wolf et al 2006]. Affected individuals have slowly progressive chronic kidney disease and minimal proteinuria. An important differentiating factor is that in MCKD1 gout usually only occurs in the setting of stage III or later chronic kidney disease. UMOD-associated kidney disease. Like FJHN2, this condition is associated slowly progressive chronic kidney disease. Persons with a UMOD-associated kidney disease do not have anemia in childhood and do not have the mild hyperkalemia often seen in FJHN2.Another condition to be considered is any form of hereditary glomerulonephritis. Affected individuals usually have proteinuria and/or hematuria. Although rarely individuals with UMOD-associated kidney disease have been found to have proteinuria, this is uncharacteristic. Fabry disease, an X-linked disorder, results from deficient activity of the enzyme α-galactosidase (α-Gal) A and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesias), the appearance of vascular cutaneous lesions (angiokeratomas), hypohidrosis, characteristic corneal and lenticular opacities, and proteinuria (which usually exceeds that seen in UMOD-associated kidney disease). Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in the third to fifth decade. Males with greater than 1% α-Gal A activity have a cardiac or renal variant phenotype. Rarely, heterozygous carrier females may have symptoms as severe as those observed in males with the classic phenotype. Gout may lead to the suspicion of chronic lead poisoning.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with familial juvenile hyperuricemic nephropathy type 2 (FJHN2), the following evaluations are recommended:Hemoglobin concentration to document the level of anemia Serum uric acid concentration to identify persons at risk for gout A 24-hour urine collection to quantify urine output and determine if polyuria is present (although this can usually determined by history). Clinical questioning regarding enuresis (bed-wetting) or frequent thirst or urination will help establish a diagnosis of polyuria. A standard basic metabolic panel to determine if hyperkalemia is present Treatment of ManifestationsAnemia may be reversed by treatment with erythropoietin [Zivná et al 2009]. This is a medication that is given subcutaneously and managed by hematologists or pediatric nephrologists. Dose is based on response to therapy. There is no clear target at this time and it is left to the discretion of the hematologist or nephrologist. Note: The dose of erythropoietin may need to be reduced as hemoglobin concentration increases during adolescence. Hyperuricemia/gout. Gout typically responds well to prednisone or colchicine. One must be careful with the use of nonsteroidal agents in individuals with REN mutations; prednisone is the preferable alternative.Treatment with allopurinol or probenecid should be considered in individuals with gout. With allopurinol treatment, serum uric acid concentration returns to normal and gout attacks can be entirely prevented. Lifelong therapy with allopurinol may be required. In individuals with allergies or intolerance to allopurinol, febuxostat may be considered; however, no data on the use of this medication in REN-associated kidney disease are available at present.Hypotension and mild hyperkalemia may be present in children and young adults with this condition. As chronic kidney disease progresses to stage III chronic kidney disease, hypertension may develop, and hyperkalemia is not due to low plasma renin activity but rather due to decreased elimination of potassium by the kidney. Therefore, treatment of low plasma renin activity/plasma concentration of aldosterone may be indicated prior to the development of stage III chronic kidney disease. Such treatment of may include liberal sodium intake if the patient has mild hypotension and hyperkalemia but preserved kidney function. Dietary sodium intake of 3 to 4 g per day may prevent hypotension. Note: A low-sodium diet should not be used in persons with FJHN2.If hyperkalemia is present, treatment with fludrocortisone or potassium restriction may be indicated [Bleyer et al 2010b]. Fludrocortisone treatment (0.1 mg orally per day) of one affected child with low plasma renin activity resulted in a mild rise in blood pressure, correction of mild hyperkalemia, and a significant improvement in estimated glomerular filtration rate, which may have been hemodynamically mediated [Bleyer at al 2010b]. The use of fludrocortisone may also prevent hypotension that could result from volume depletion such as that associated with viral syndromes or vigorous activities associated with excessive perspiration. Note: Fludrocortisone treatment in two adults with advanced kidney disease had no clinical effect.Fludrocortisone could have the advantage of decreasing renin production (through negative feedback), and thus the production of the abnormal renin deposits. However, since blockade of the renin angiotensin system and aldosterone production has been a general treatment of chronic kidney disease, it is possible that increased serum concentration of aldosterone may increase progression of renal disease. Thus, while the use of fludrocortisone may potentially be beneficial in this condition, at present its use is at the discretion of the clinician.Mineralocorticoid replacement. Recommendations regarding treatment are not evidence-based due to the small number of individuals with this disorder and the limited experience treating affected individuals. Renal disease. Referral to a nephrologist is indicated to monitor kidney function, evaluate for manifestations of chronic kidney disease, and prepare for renal replacement therapy when renal insufficiency occurs. Renal replacement therapies such as hemodialysis and peritoneal dialysis replace renal function but are associated with potential complications.Kidney transplantation cures FJHN2. The transplanted kidney does not develop the disease.Prevention of Primary ManifestationsTreatment with erythropoietin can reverse anemia [Zivná et al 2009]. Treatment of hyperuricemia with allopurinol can prevent development of gout.Prevention of Secondary ComplicationsIron stores should be replenished as needed to treat iron deficiency (an unrelated condition) if it is present.SurveillanceMeasurement of hemoglobin concentration and serum concentration of uric acid and creatinine annually starting at the time of diagnosis. Agents/Circumstances to AvoidThe use of nonsteroidal anti-inflammatory medications (NSAIDs) should be avoided, especially in persons who are dehydrated. The use of NSAIDs in a febrile child with FJHN2 precipitated acute renal failure [Bleyer et al 2010b]. The use of other analgesics/antipyretics should be considered.It would appear that the use of an angiotensin-converting enzyme inhibitor may not be beneficial in the treatment of chronic kidney failure and could aggravate the underlying relative renin deficit.Volume depletion and dehydration may worsen hyperuricemia and lead to more frequent attacks of gout.High meat and seafood intake could exacerbate gout.Exertion under extreme conditions (such as physical exertion when it is hot) should be avoided.Evaluation of Relatives at RiskIf the REN mutation has been identified in an affected family member, it is appropriate to consider molecular genetic testing of at-risk relatives particularly:Children because of their increased risk for anemia;Adolescents because of their increased risk for gout, which can be prevented with allopurinol treatment;Relatives interested in donating a kidney to an affected family member.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Successful pregnancies have been documented in women with a REN mutation. The rate of miscarriages or other adverse outcomes was not increased. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Familial Juvenile Hyperuricemic Nephropathy Type 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDREN1q32​.1ReninREN homepage - Mendelian genesRENData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Familial Juvenile Hyperuricemic Nephropathy Type 2 (View All in OMIM) View in own window 179820RENIN; REN 613092HYPERURICEMIC NEPHROPATHY, FAMILIAL JUVENILE, 2; HNFJ2Molecular Genetic Pathogenesis In vitro studies have shown that the presence of the mutated signal peptide affects targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER) and, thus, proper biosynthesis and intracellular trafficking of prorenin. This results in ER stress, cytosolic accumulation of abnormal non-glycosylated preprorenin, accelerated autophagocytosis, and reduced growth rate. In vivo this gradually reduces viability of renin-producing juxtaglomerular cells, and results – by not-yet defined mechanism(s) – in tubular atrophy, nephron loss, and chronic kidney failure, similar to that observed in mice with ablated juxtaglomerular cells [Pentz et al 2004]. The REN mutation also results in decreased renin production, a goal of therapy for many chronic kidney diseases. Thus, the disease becomes its own treatment. Normal allelic variants. REN is located on chromosome 1 (genomic position chr1:204123944-204135465; according to GRCh37/hg19 [Feb 2009] assembly). The gene comprises ten exons, which are transcribed into a 1493-bp long transcript encoding for 406 amino-acid preprorenin (Reference sequence NM_000537.3).Pathologic allelic variants. Only missense mutations and/or small insertions/deletions affecting renin biosynthesis and trafficking are expected to cause FJHN2. Mutations in exons 1 and 2 are expected to account for most mutations that result in FJHN2. Normal gene product. Renin is normally produced by modified juxtaglomerular cells of the afferent arterioles in the macula densa of the kidney. Renin cleaves the N-terminal ten amino acids of angiotensinogen to produce angiotensin I, which is further converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II stimulates aldosterone production. Through a number of mechanisms, renin and angiotensin help to maintain normal blood pressure and to lower serum potassium concentrations into the normal range.Abnormal gene product. Familial juvenile hyperuricemic nephropathy type 2 is caused by REN mutations predominantly in the signal sequence of the protein renin, affecting targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). This leads to reduced expression of renin and other components of the renin angiotensin system in kidney biopsy specimens of affected individuals. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intra-renal renin-angiotensin system and the functionality of the juxtaglomerular apparatus, resulting in nephron dropout and progressive kidney failure.