BUKU PEGANGAN TUTOR

Modul BENGKAK PADA WAJAH

DAN PERUT

Diberikan pada mahasiswasemester IV FK UNHAS

SISTEM UROGENITALIAFAKULTAS KEDOKTERAN

UNIVERSITAS HASANUDDINMAKASSAR

2005

PENDAHULUAN

Modul bengkak pada wajah dan perut ini diberikan pada mahasiswa yang

mengambil mata kuliah sistim Urogenitalia di semester IV. TIU dan TIK pada sistim ini

disajikan pada permulaan buku modul agar dapat dimengerti secara menyeluruh tentang

konsep dasar penyakit-penyakit Sistem Urogenitalia yang memberikan gejala bengkak

pada wajah dan perut. Mahasiswa diharapkan mampu menjelaskan semua aspek tentang

system Urogenitalia dan patomekanisme terjadinya penyakit, kelainan jaringan, dan

pemeriksaan lain yang dibutuhkan pada penyakit yang memberikan gejala bengkak pada

wajah dan perut..

Sebelum menggunakan modul ini, mahasiswa diharapkan membaca TIU dan TIK

sehingga tidak terjadi penyimpangan pada diskusi dan tujuan serta dapat dicapai

kompetensi minimal yang diharapkan. Bahan untuk diskusi dapat diperoleh dari bacaan

yang tercatum di akhir modul. Kuliah pakar akan diberikan atas permintaan mahasiswa

yang berkaitan dengan penyakit ataupun penjelasan dalam pertemuan konsultasi antara

peserta kelompok diskusi mahasiswa dengan tutor atau ahli yang bersangkutan.

Penyusun mengharapkan modul ini dapat membantu mahasiwa dalam

memecahkan masalah penyakit Urogenitalia yang disajikan.

Makassar, 2 Desember 2005

Penyusun

TUJUAN INSTRUKSIONAL UMUMSetelah pembelajaran modul ini selesai, mahasiswa diharapkan dapat menjelaskan

tentang penyakit-penyakit yang menyebabkan pembengkakan pada muka dan perut,

serta gejala-gejala klinis, penyebab, patomekanisme, cara-cara diagnosis,

penatalaksanaan/terapi, komplikasi dan aspek epidemiologi penyakit-penyakit yang

menyebabkan pembengkakan pada muka dan perut .

TUJUAN INSTRUKSIONAL KHUSUS

Setelah pembelajaran dengan modul ini mahasiswa diharapkan dapat :

1. Menguraikan struktur anatomi, histologi dan histofisologi dari sistim uropoetika

2. Menyebutkan fungsi masing-masing bagian dari nefron, fungsi sel-sel JGA dalam

renin angiotensin system,

3. Menjelaskan faktor-faktor yang mempengaruhi GFR, prinsip hukum Starling pada

filtrasi ginjal, proses reabsorbsi dan sekresi di ginjal

4. Menjelaskan perubahan biokimia urine dan kompensasi ginjal dalam

keseimbangan asam basa

5. Menjelaskan penyakit-penyakit yang dapat memberikan gejala bengkan pada

wajah dan perut baik pada penderita anak-anak maupun dewasa

6. Menjelaskan patomekanisme timbulnya gejala bengkak pada wajah dan perut

7. Menjelaskan cara anamnesis, pemeriksaan fisis, dan pemeriksaan penunjang yang

dibutuhkan untuk mendiagnosis banding beberapa penyakit yang mempunyai

gejala bengkak pada wajah dan perut

8. Mampu melakukan pemeriksaan laboratorium sederhana untuk pemeriksaan

penyakit-penyakit sistem Urogenitalia

9. Mampu menganalisa hasil laboratorium dan pemeriksaan radiologik (BNO dan

IVP) pada penderita penyakit sistim Urogenitalia

10. Menjelaskan penatalaksanaan penderita-penderita sistem Urogenitalia terutama

yang memberikan gejala bengkak pada wajah dan perut

11. Menjelaskan asuhan nutrisi yang sesuai untuk penyakit-penyakit sistim

Urogenitalia terutama yang memberikan gejala bengkak pada wajah dan perut

12. Menjelaskan epidemiologi dan tindakan-tindakan pencegahan penyakit-penyakit

sistim urogenitalia, terutama yang memberikan gejala bengkak pada wajah dan

perut

PROBLEM TREE

Lab : Urine Kimia darah UrinalisisPemeriksaan lain : CT ginjalPatologi Anatomi

Diagnosis Banding KwashiorkorGlomerulonephritis Angioedema Heart Failure, Congestive Obesity Protein-Losing Enteropathy Proteinuria

Anamnesis :Bengkak pada wajah dan perut.Sejak 3 minggu

Fisik Diagnostik :Odem pada wajah & perut

BENGKAK PADA WAJAH & PERUT

AnatomiHistologiFisiologiBiokimia Patologi Anatomi Farmakologi

Bedah

Medikamentosa Non Medikamentosa Nutrisi

Penatalaksanaan Pengendalian

Preventif Promotif Non Bedah

Prognosis Komplikasi

Skenario: Bengkak pada wajah dan perut

1. Setelah membaca dengan teliti skenario di atas anda harus mendiskusikan kasus

tersebut pada satu kelompok diskusi terdiri dari 12 – 15 orang, dipimpin oleh seorang

ketua dan seorang penulis yang dipilih oleh anda sendiri. Ketua dan sekretaris ini

sebaiknya berganti-ganti pada setiap kali diskusi. Diskusi kelompok ini bisa dipimpin

oleh seorang tutor atau dilakukan secara mandiri oleh kelompok.

2. Melakukan aktivitas pembelajaran individual di perpustakaan dengan menggunakan

buku ajar, majalah, slide, tape atau video, dan internet, untuk mencari informasi

tambahan.

3. Melakukan diskusi kelompok mandiri (tanpa tutor) , melakukan curah pendapat bebas

antar anggota kelompok untuk menganalisa dan atau mensintese informasi dalam

menyelesaikan masalah.

4. Berkonsultasi pada nara sumber yang ahli pada permasalahan dimaksud untuk

memperoleh pengertian yang lebih mendalam (tanpa pakar).

5. Mengikut kuliah khusus (kuliah pakar) dalam kelas untuk masalah yang belum jelas

atau tidak ditemukan jawabannya.

6. Melakukan latihan dilaboratorium keterampilan klinik dan praktikum di laboratorium.

Seorang anak laki-laki, 12 thn, dating ke Puskesmas dengan bengkak pada wajah dan perut. Keadaan ini dialami sejak 3 minggu yang lalu dan saat ini semakin bertambah .

TUGAS MAHASISWA

PROSES PEMECAHAN MASALAH

Dalam diskusi kelompok dengan menggunakan metode curah pendapat, mahasiswa

diharapkan memecahkan problem yang terdapat dalam skenario ini, yaitu dengan

mengikuti 7 langkah penyelesaian masalah di bawah ini:

1. Klarifikasi istilah yang tidak jelas dalam scenario di atas, dan tentukan kata/ kalimat

kunci skenario diatas.

2. Identifikasi problem dasar scenario diatas dengan, dengan membuat beberapa

pertanyaan penting.

3. Analisa problem-problem tersebut dengan menjawab pertanyaan-pertanyaan diatas.

4. Klasifikasikan jawaban atas pertanyaan-pertanyaan tersebut di atas.

5. Tentukan tujuan pembelajaran yang ingindi capai oleh mahasiswa atas kasus

tersebut diatas.

6. Cari informasi tambahan tentang kasus diatas dari luar kelompok tatap muka.

Langkah 6 dilakukan dengan belajar mandiri.

7. Laporkan hasil diskusi dan sistesis informasi-informasi yang baru ditemukan.

Langkah 7 dilakukan dalm kelompok diskusi dengan tutor.

Penjelasan :

Bila dari hasil evaluasi laporan kelompok ternyata masih ada informasi yang

diperlukan untuk sampai pada kesimpulan akhir, maka proses 6 bisa diulangi, dan

selanjutnya dilakukan lagi langkah 7.

Kedua langkah diatas bisa diulang-ulang di luar tutorial, dan setelah informasi

dirasa cukup maka pelaporan dilakukan dalam diskusi akhir, yang biasanya dilakukan

dalam bentuk diskusi panel dimana semua pakar duduk bersama untuk memberikan

penjelasan atas hal-hal yang belum jelas.

1. Pertemuan pertama dalam kelas besar dengan tatap muka satu arah dan tanya jawab.

Tujuan : menjelaskan tentang modul dan cara menyelesaikan modul, dan membagi

kelompok diskusi. Pada pertemuan pertama buku modul dibagikan.

2. Pertemuan kedua : diskusi mandiri. Tujuan :

* Memilih ketua dan sekretaris kelompok,

* Brain-storming untuk proses 1 – 3,

* Membagi tugas

3. Pertemuan ketiga: diskusi tutorial dipimpin oleh mahasiswa yang terpilih menjadi

ketua dan penulis kelompok, serta difasilitasi oleh tutor. Tujuan: untuk melaporkan

hasil diskusi mandiri dan menyelesaikan proses sampai langkah 5.

4. Anda belajar mandiri baik sendiri-sendiri. Tujuan: untuk mencari informasi baru yang

diperlukan,

5. Pertemuan keempat: adalah diskusi tutorial. Tujuan: untuk melaporkan hasil diskusi

lalu dan mensintese informasi yang baru ditemukan. Bila masih diperlukan informasi

baru dilanjutkan lagi seperti No. 2 dan 3.

6. Pertemuan terakhir: dilakukan dalam kelas besar dengan bentuk diskusi panel untuk

melaporkan hasil diskusi masing-masing kelompok dan menanyakan hal-hal yang

belum terjawab pada ahlinya (temu pakar).

TIME TABLE

PERTEMUANI II III IV V VI VII

Pertemuan I(Penjelasan)

Pertemuan Mandiri(Brain

Stroming)

Tutorial I Pengum-

pulan informasiAnalisa &

sintese

Mandiri

PraktikumCSL

Kuliah kosultasi

Tutorial II(Laporan &

Diskusi)

Pertemuan Terakhir (Laporan)

JADWAL KEGIATAN

STRATEGI PEMBELAJARAN

1. Diskusi kelompok difasilitasi oleh tutor

2. Diskusi kelompok tanpa tutor

3. CSL : Pemeriksaan benjolan pada leher

4. Praktikum PA

5. Konsultasi pada pakar

6. Kuliah khusus dalam kelas

7. Aktivitas pembelajaran individual diperpustakaan dengan menggunakan buku ajar

Majalah,slide,tape atau video dan internet

A. Buku Ajar dan Jurnal

1 Campbell's Urology, W.B.Saunders Co.2 General Urology, D.R.Smith, Lange Medical Book3 Grant BJC The perineum and Pelvis : a Method of Anatomy4 Grant Henry and Mayo Goss. The Urogenital System5 Kenneth J Rothman, 1986, Modern Epidemiology, Little Brownc and Company, Bon 6 World Health Organization, 1992, International statistical Classification of Diseases

an and related Health Problems, 10th revision, volume 1, WHO, Geneva

7 Goodharmt R : Modern nutrition in health and disease, Lee Ferbeger, 20028 Robinson : Normal and Therapeutic Nutrition, Mac Millian Co., New York9 Baron et.al. : Diagnostic Microbiology, 9th edition, Mosby Co, 1994

10 Prescott LM et al : Microbiology, 2nd edition, Wm.c Brown Publisher, Melbourne, 1993

11 Parker and Collier : Principles of Bacteriology, Virology & Immunity, 8th edition, vol 1-5, 1990

12 Guyton & Hall : Textbook of Medical Physiology, edisi 10, 2001 13 A Textbook of Radiology and Imaging : David Sutton, 199314 Junguiera LC, Carneiro J : Basic Histology 3th edition, Los Altos California USA,

Lange Medical Publication, 198015 Thorpe, Neal O : Cell Biology 5th edition, Canada, John Wiley and Son Inc, 198416 Stites DP, Stobo JD, Fudenberg HH : basic and Clinical Immunology, 4th edition, Los

Altos California, Lange Medical Publication, 1982

17 Schlesinger ER, Sultz HA, Mosher WE, et al. The Nephrotic Syndrome. Its incidence and implications for the community. Am J Dis Child 1968, 116; 623

18 Wila Wirya IGN. Penelitian beberapa aspek klinis dan patologi anatomis sindrom nefrotik primer pada anak di Jakarta. Disertasi, 1992

19 International Study of Kidney Disease in Children. Nephrotic Syndrom in Children.

BAHAN BACAAN & SUMBER INFORMASI LAIN

Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int. 1978, 13: 159.

20 Mohammad SN. Glomerulonefritis. Dalam buku ajar nefrologi anak. Balai penerbit FKUI, Jakarta 2002, 345-52

21 Drum-mond KN. Infection of the urinary tract, dalam: Vaughan VC, MC Kay RJ, Behrman RE, penyunting. Nelson Textbook of pediatrics, Edisi 11, Tokyo : Igoku Shoin, 1979: 1543-48

22 Kallen RJ. UTI: Treating the first infection and avoiding the second, Mod med Asia, 1980; 16: 67-74

23 McCracken GH. Diagnosis and management of acute urinary tract infections in infants and children. J Pediatric infection disease. 1987; 107-112

24 Kher KK. Obstructive uropathy. Dalam : Kher KK, Marker SP, penyunting. Clinical Pediatric Nephrology. New York: Mc Graw – Hill 1992: 447-65.

25 Behrman RE. Nelson textbook of pediatrics; edisi ke 14. Philadelphia: WB Saunders, 1992; 1344-50.

26 Homes HD, Weinberg JM. Toxic nephropathies. Dalam: Brenner Rector FC, penyunting, The Kidney, II; edisi ke-Philadelphia: WB Saunders Co, 1986; 1491-532.

27 Kher KK. Chronic renal failure. Dalam Kher KK, Marker SP, penyunting, clinical pediatric nephrology. New York: MC Graw-Hill Inc, 1992, 501-41.

28 Meatow SR. Eneuresis. Dalam: Pediatric Kidney Disease. Edelman CM, penyunting. Edisi 2, Boston: Little Brown Co 1992: 105-84

29 Londe S causes of hypertension in the young. Pediatric Clin North Am 1978; 25-55.30 Harrison : Disorders of the kidney and Urinary tractus, 15th edition, Volume I, Mc

Graw Hill, 2002, pp : 1535-1630

A. Diktat dan hand-out

1. Diktat Anatomi Diktat Histologi Buku Ajar Fisiologi Ginjal Diktat Kuliah Radiologi

B. Sumber lain : VCD, Film, Internet, Slide, Tape

C. Nara sumber (Dosen Pengampu)

DAFTAR NAMA NARA SUMBER

No. NAMA DOSEN BAGIAN TLP. KANTOR

HP/FLEXI

1. Prof.Dr. dr. Syarifuddin Rauf Sp.PA

Anak 0811411109

2. Prof.Dr.dr. Syakib Bakri, Sp.PD

Penyakit Dalam 0816250620

3. Prof.dr. Ahmad M Palinrungi Sp.B, Sp.U

Bedah Urologi 08164384040

4. Prof.Dr.dr. M.Dali Amiruddin, Sp.KK

Kulit Kelamin 08194229858

5. Dr. Irfan Idris, MS Fisiologi 584730 0813426953486. Dr. Theopilus Buranda, MS Anatomi 0813424364447. Dr. Robby Lianury Histologi 08114117238. Dr. Agnes Kwenang, MS Biokimia9. Dr. dr. Gatot Lawrence Patologi

Anatomi0816255306

10. Dr. dr. Nurpudji Astuti, SpGK

Gizi 0811443856

11. Dr. dr. Fatmawati Farmakologi 08152412036812. Dr. Randana Bandaso, MS Patologi

Anatomi13. Dr. Nurlaily Idris, Sp.R Radiologi 081144106414. Dr. H, Ibrahim Samad, SpPK Patologi Klinik15. Dr. Baedah Madjid, SpMK Mikrobiologi 081144432616. Dr. Sastri, SpKK Kulit Kelamin 08124217393

A. Kata/kalimat kunci

1. Anak laki-laki

2. 12 tahun

3. Bengkak pada wajah dan perut

4. Pembengkakan makin bertambah

B. Beberapa pertanyaan prinsip dan jawaban alternatifnya

Apa yang dimaksud dan mekanisme ‘kata kunci’ berikut ini :

1. Pria umumnya lebih banyak dari wanita dengan perbandingan 2:1 dan

beberapa studi mendapatkan 3 : 2 pada kejadian Sindroma Nefrotik.

2. Umur 12 tahun : Pada kejadian Sindroma Nefrotik 75% terjadi pada umur <

18 tahun dengan onset pada umur < 6 thn.

3. Bengkak pada wajah & perut : Wajah tampak mengembang akibat

akumulasi cairan terutama pada daerah jaringan yang resistensinya kurang

seperti daerah preorbital (pada wajah), skrotum dan labia. Udema jika

sangat berat (massif) dapat terjadi anasarka termasuk udema di perut. Hal ini

terjadi akibat hipoproteinemia sehingga terjadi extravasasi cairan menuju

ruang interstitiel.

4. Pembengkakan makin bertambah : derajat udema makin berat. Pada

penyakit SN udema cenderung makin bertambah berat. Mekanismenya

belum jelas, beberapa sarjana mengatakan bahwa selain terjadi

hipoalbunemia, juga terjadi penigkatan sekresi aldosteron, vasopressin, dan

menurunnya ANP yang menyebabkan resistensi air dan garam.

Apa penyebab dan bagaimana pato-mekanisme gejala-gejala yang menjadi kata

kunci tersebut

PETUNJUK UNTUK TUTOR

1. Udema : Terjadi akibat hipoproteinemia, terutama fraksi albumin

(hipoalbuminemia). Menurunnya kadar protein menyebabkan menurunnya

tekanan osmotik protein plasma. Hal ini akan menyebabkan cairan

intravaskuler menuju ke ruangan interstitiel akibat perbedaan osmotik

protein di ruangan interstitiel lebih tinggi dibanding dalan pembuluh

darah. Menurunnya cairan intravaskuler menyebabkan rangsangan renin-

angiotensin-aldosteron sistem. Kemudian terjadi perangsangan pada ADH

sehingga terjadi penahanan air dan garam, hal inilah yang menyebabkan

udem.

2. Udema yang makin bertammbah : meskipun belum jelas, tetapi beratnya

udem diperparah oleh aktifnya renin-angiotensin-aldosteron sistem

sehingga ginjal menahan air dan garam.

Sebutkan beberapa penyakit yang dapat di differential diagnosis

dengan tanda dan gejala pada skenario

1. Acute Poststreptococcal Glomerulonephritis 2. Angioedema 3. Heart Failure, Congestive 4. Nephritis 5. Nephrotic Syndrome 6. Obesity 7. Oliguria 8. Protein-Losing Enteropathy 9. Proteinuria 10. Systemic Lupus Erythematosus

Pemeriksaan penunjang yang dibutuhkan untuk menegakkan diagnosis penyakit

yang termasuk dalam DD penyakit tersebut

1. Urinalisis : hematuria, protein, ratio UA/G

2. Kimia darah : hipoalbuminemia, hyperlipidemia,

3. Radiologi : Thorax foto :pleural effusion, USG renal

4. Biopsi ginjal

Bagaimana cara penatalaksanaan dari penyakit-penyakit yang termasuk dalam

DD penyakit tersebut

1. Medikamentosa : steroid, diuretik, anti infeksi, antihipertensi

2. Diet

Epidemiologi dan cara pencegahan penyakit tersebut

1. Insidens 2-5 per 100.000 anak dibawah 18 tahun. Prevalensinya di USA

dilaporkan 15.5 per 100.000 anak.

2. Relaps adalah hal yang dapat diusahakn untuk dicegah. Biasanya relaps

mudah terjadi setelah infeksi saluran napas, sehingga pencegahan infeksi

saluran nafas perlu dilakukan.

3. Relaps mudah terjadi setelah imunisasi rutin, sehingga imunisasi perlu

ditunda sampai remisi terjadi.

Komplikasi penyakit-penyakit yang termasuk DD pada skenario

1. Lesi glomerulus

2. Hypoproteinemia

3. Efek pemberian steroid

Prognosis penyakit-penyakit tersebut

Tergantung pada hasil pemeriksaan histologis ginjal. Penderita yang memberi respon pada steroid umumnya mengalami relaps yang tidak sering. Tetapi penderita yang tidak memberi respon terhadap steroid lebih sering mengalami relaps.

Nephrotic Syndrome

Background: The word nephrosis, or what often is called primary nephrotic syndrome (PNS), has its origin in the early part of the 20th century. Nephrosis describes a clinical condition of edema and proteinuria characterized morphologically (light microscopy [LM]) by fatty degeneration of the renal tubules associated with normal glomeruli. The term nephrosis was introduced primarily to distinguish it from nephritis, a term used to denote the clinical condition associated with cellular proliferation of the glomerulus. Shortly thereafter the name of the condition was changed to lipoid nephrosis when it was noted that lipid droplets commonly were found in the urine of affected patients. Lipoid nephrosis gradually evolved to the present name of nephrotic syndrome (NS).

NS is a clinical condition characterized by massive urinary loss of protein (primarily albumin), which leads to hypoproteinemia (hypoalbuminemia) and edema. Hyperlipidemia, hypercholesterolemia, and increased lipiduria usually are associated. Although not commonly thought of as part of NS, hypertension, hematuria, and azotemia may occur. NS is categorized into primary and secondary forms. The name PNS has replaced, in some circles, the older designation (idiopathic), but it implies the same vagueness as to cause. Included are a wide variety of clinical as well as pathologic states, some of which are noted in Synonyms. The term secondary NS is associated with more clearly defined diseases, such as anaphylactoid purpura, systemic lupus erythematosus, diabetes mellitus, sickle cell disease, and syphilis. Most attention in this article is devoted to PNS because of its relative frequency in children.

Histopathologic characteristics led to the description of PNS subcategories, some associated with specific clinical manifestations. Currently, knowledge regarding etiology precludes a more precise classification. Nevertheless, in the following sections, the variants of PNS are considered as if they are disease entities with well-defined clinical and histopathologic characteristics; the histologic type at onset makes generalization about the response to therapy and the ultimate prognosis possible. When possible, the definitions, descriptions, and nomenclature developed by the International Study of Kidney Diseases in Children (ISKDC) are used. Most attention is devoted to minimal change nephrotic syndrome (MCNS), immunoglobulin M (IgM) mesangial nephropathy, and focal segmental glomerulosclerosis (FSGS), with modest attention to familial or congenital nephrosis, membranoproliferative glomerulonephritis (MPGN), and membranous nephropathy (MN).

MCNS is the most common form of NS in children, and its prevalence is inversely proportional to the age at onset; beyond infancy, the likelihood that the histology demonstrates minimal abnormalities on LM evaluation of glomerular histology increases with younger age. As is discussed later, within this category, histologic variations exist in which some patients demonstrate only fusion and smudging of the epithelial cell podocytes, while others may demonstrate mild changes within the glomerular mesangium, consisting of either slight proliferation or sclerosis. Because patients with MCNS have the highest rate of responsiveness to standard therapy and the best long-term prognosis, separating them from others is important.

IgM mesangial nephropathy may be a separate entity from MCNS. The current histologic criteria of NS are based predominately on LM findings. During the study period, the ISKDC did not use immunofluorescent microscopy in defining histologic criteria. Most patients who have significant IgM staining of the mesangium present in a similar manner to those with MCNS, unless coexistent mesangial proliferation is present. Controversy exists as to whether IgM mesangial deposition in a patient with minimal changes on LM affects either the response to therapy or the subsequent clinical course.

FSGS is heterogeneous condition; much of the confusion in the literature is the result of attempts by some authors to portray it as a single entity. FSGS is a histopathologic expression of a variety

of conditions, each with its own clinical manifestations. The lesion may be observed at the onset of an otherwise typical case of NS, or it may be discovered only after years of nephrosis in a patient in whom the initial biopsy was compatible with MCNS, but whose course of the disease suggested otherwise. FSGS may be the consequence of glomerular hyperfiltration in patients with reflux nephropathy and in some patients with a single kidney.

MPGN may present as a NS, particularly in older children and adolescents. MPGN usually is associated with a nephritic picture although, on occasion, MPGN may appear similar to MCNS or FSGS.

While membranous glomerulonephritis (MGN) occurs in children, it is exceedingly rare in children younger than 10 years, and most incidents of MGN occur in adolescents. MGN usually is idiopathic in origin; however, a number of well-defined etiologies have been described, and the competent physician is prudent to consider these secondary causes in the evaluation. MGN is not associated infrequently with hepatitis B and has been described with both hepatitis A and hepatitis C. In parts of the world where malaria is prevalent, the most common renal lesion associated with malaria is MGN. MGN also has been associated etiologically with HIV infections. In the young person, the heavy proteinuria often is accompanied by hematuria. This lesion responds poorly to glucocorticoid therapy and often is suspected first when the patient is unresponsive to standard steroid management (see Medical Care).

Congenital nephrotic syndrome must be considered when nephrosis appears during the first year of life, particularly during the first few months.

Pathophysiology: Heavy proteinuria (albuminuria) is the hallmark and primary abnormality of NS. The degree of proteinuria varies considerably from one child to another and is proportional, at least in part, to plasma protein concentration. Thus, a child with active NS who has a serum albumin concentration of 2 g/dL usually excretes a larger amount of albumin than a similar child with a serum albumin concentration of 0.5 g/dL. Some children excrete as much as 15 g/m2/d, although the minimal excretion rate compatible with the diagnosis of NS is approximately 1 g/m2/d (approximately 40 mg/m2/h).

The event that produces proteinuria is unknown. In MCNS, the glomerular capillary permeability to albumin is increased selectively, whereas proteinuria is nonselective in other forms of NS, such as those associated with nephritic features. The increase in the filtered load of protein overcomes the modest ability of the tubules to reabsorb it, and proteinuria ensues. The albumin selectivity observed in persons with MCNS may be due in part to the smaller size of the molecule; however, the absence of increased excretion of some smaller-weight plasma proteins makes this explanation insufficient. One possible explanation is the disappearance of negative charges normally present along the glomerular capillary endothelium and basement membrane. This disappearance allows the negatively charged albumin to traverse the glomerular capillary barrier. This has been demonstrated in experimental nephrosis and in some children with PNS.

PNS is believed to have an immune pathogenesis, but the nature of this immune process has yet to be defined completely. A highly cationic plasma protein that may neutralize the anionic charge on the glomerular capillary wall has been described in children with NS. Other investigators have noted a decrease in immune responsiveness and have related this to alterations in either T- lymphocyte number and/or function. The presence of suppresser cytokines or lymphokines has been postulated, and various investigators have demonstrated changes in interleukin-8, interferon permeability factor, and vascular permeability factor. The role of the kinin system also is under investigation because urinary excretion of kinins is increased during exacerbations of the disease.

Hypoalbuminemia is mainly the result of the increased urinary loss of protein; however, other factors may contribute to the hypoalbuminemia, such as decreased synthesis, increased

catabolism, and increased gastrointestinal losses. Even though most studies have demonstrated that the albumin synthesis rate is not decreased, the capacity to increase hepatic production appears insufficient to compensate for the large urinary losses.

The classic explanation for the edema formation is that low-serum albumin causes a decrease in plasma oncotic pressure (POP) with extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume (PV) theoretically leads to a decrease in renal perfusion and, hence, to stimulation of the renin-angiotensin system. This hormonal effect coupled with an increase in the synthesis and secretion of antidiuretic hormone (related to the decrease in effective PV) affects the renal tubular reabsorption of sodium and water. The results of these disturbances are a reduction in renal perfusion (eg, glomerular filtration rate [GFR]) and an increased hormonal activity that leads to avid reabsorption of both sodium and water.

While the hypothesis described above is attractive, some experimental data fail to support it. First, the PV is not always decreased, and, in most adults, PV appears to be increased. Only in young children with MCNS have most studies revealed a reduced PV. Most investigators have failed to document elevated levels of renin, angiotensin, or aldosterone even during times of avid sodium retention. Moreover, retention of sodium continued despite maneuvers that suppress renin (eg, albumin infusion) or aldosterone synthesis (angiotensin-converting enzyme inhibitor administration). Coupled with these discrepancies is the fact that, in steroid-responsive NS, diuresis usually begins before the plasma albumin has increased significantly and before POP has changed. Some investigators reported a blunted response to atrial natriuretic peptide despite higher than normal circulating levels of atrial natriuretic peptide.

Thus, the precise causes of the edema and of its persistence remain uncertain. A complex interplay of a variety of physiologic factors (eg, decreased POP, increased activity of aldosterone and vasopressin, diminished atrial natriuretic hormone, activities of various cytokines, physical factors within the vasa recti) probably contributes to the retention of sodium and the accumulation of water.

Mortality/Morbidity:

The mortality rate depends almost entirely on the type of disease causing the heavy urinary loss of albumin. The long-term prospect of complete remission in persons with MCNS is greater than 70% with a reported cumulative mortality rate (at 20 y postonset) of less than 15% (range in various studies is 5-15%). Conversely, only 24% of patients with FSGS are in remission after 20 years, and the cumulative mortality rate is greater than 50% (see Prognosis).

The morbidity rate is substantial. Even in its mildest form, MCNS often is a chronic disease that requires the following:

o Hospitalization, in some instanceso A prolonged period of treatmento Frequent monitoring both by parents and by physician o Administration of drugs associated with significant adverse eventso A high rate of recurrence (ie, relapses in >60% of patients) o The potential for progression to chronic renal failure (CRF)

In patients who demonstrate multiple relapses, the potential problems are associated with the need for long-term immunosuppression therapy that predisposes to serious infections, decreases in growth velocity, behavioral changes, obesity, cataracts, hypertension, osteoporosis, osteomalacia, nephrolithiasis, diabetes mellitus, hirsutism, gingival hypertrophy, and other issues.

Sex:

In children younger than 8 years at onset, the ratio of males to females is 2:1 to 3:2 in various studies.

In older children, adolescents, and adults, the male-to-female prevalence is approximately equal.

ISKDC data indicate that 66% of patients with either MCNS or FSGS are male, whereas for individuals with MPGN, 65% are female.

Age: Approximately 75% of the patients who developed NS when younger than 18 years were younger than 6 years at onset. MCNS is primarily an illness of preschool children, with peak incidence occurring when the child is aged 3-4 years, although MCNS onset may occur at any age. With the exception of the first year of life, the likelihood that the lesion is MCNS increases with younger age at onset. When disease onset occurs when the child is younger than 5 years, the likelihood that the lesion is MCNS is greater than 90%, while the risk of FSGS and MPGN is 7% and 1%, respectively. Conversely, when disease onset occurs when the individual is older than 10 years, the risk of MCNS drops to approximately 50%, and the risk of MPGN approaches 30%. FSGS may occur at any age; however, its incidence tends to increase slightly with advancing age.

CLINICAL

History:

Edema: Regardless of the type of NS (ie, histopathologic type), the major clinical manifestation is edema, which is a presenting symptom in approximately 95% of children with NS.

o Edema often is so insidious in onset that the family may believe the child merely is gaining weight rapidly.

o Edema in the early phase may be intermittent; it usually appears first in areas of low tissue resistance (eg, periorbital area, scrotal and labial regions). Ultimately, the edema becomes generalized and can be massive (anasarca).

o Because the nature of edema is typically dependent, edema often is worse in the face in the morning (upon arising) and is found predominantly in the lower extremities later in the day.

o The edema is pitting in nature.

o In individuals with marked edema, the skin may ooze clear fluid and appear thinner than usual. Breakdown of the tissue is common.

o Edema usually is more marked in the patient with MCNS than in the patient with either FSGS or MPGN. This is because urinary protein loss and hypoproteinemia are virtually always greater in persons with MCNS.

Age of appearance: The child with congenital NS often presents earlier than the child with MCNS, but the age of appearance of the first signs of disease overlap significantly.

Hematuria

o An occasional child with NS presents with gross hematuria.

o The frequency of macrohematuria depends on the histologic subtype of NS.

o Macrohematuria is more common in patients with MPGN; however, even in individuals with MCNS, the frequency of macrohematuria has been reported as high as 3-4%.

o Statistically, a higher percentage of patients with FSGS have microhematuria than those with MCNS at presentation; however, this statistic is not very helpful in differential diagnosis.

o The persistence of microscopic hematuria beyond the first month, which is common in persons with FSGS but seldom observed in individuals with MCNS, is more relevant.

Oliguria: Oliguria is a common occurrence during relapses. Underlying renal involvement: More specific clinical manifestations occur at various

frequencies, depending on the type of underlying renal involvement (see Lab Studies, Histologic Findings).

Common symptoms: Regardless of the type of NS, patients commonly are anorexic, irritable, fatigued, and complain of abdominal discomfort, which is believed to be related to edema of the bowel wall.

o Patients commonly complain of diarrhea, which also is believed to be related to edema of the bowel wall.

o If ascites is marked, patients commonly complain of respiratory distress.

Fever and infection

o An occasional child presents with fever and a septic picture. o In a number of these patients, the peritoneal cavity is the site of the infection. o Streptococcus pneumoniae still is the most frequent organism responsible for

peritonitis in this population, but Staphylococcus aureus and Escherichia coli commonly are recovered.

o A urinary tract infection occasionally is present and may be responsible for the lack of response to therapy.

o A history of respiratory tract infection (RTI) immediately preceding the first clinical signs of the disease may exist, but its relevance is uncertain.

Allergies

o A history of prior allergic events is common, and atopy has been reported in approximately 40-50% of children with MCNS.

o A hypersensitive event (eg, insect sting, ant bites, poison ivy, immunizations) has preceded the onset in some individuals and may be considered etiologically significant.

o The peak incidence of NS appears to be seasonally related, at least in certain geographic areas.

o A few children have been reported with major food allergies, and, in some, ultimate remission was associated with dietary elimination programs.

Physical:

The most common clinical finding in all patients with NS is edema, which is present in more than 95% of individuals with the condition.

o The degree of edema usually is greatest in patients with MCNS.

o When mild, edema is localized to those areas where tissue resistance is low (eg, periorbital area, scrotum, labia).

o Generalized edema is dependent and pitting in character.

o Ascites is common, and anasarca may be present. In children with marked ascites, mechanical restriction of breathing may be present, and the child may have compensatory tachypnea.

o Due to the skin edema, the child usually appears paler than laboratory evidence of anemia suggests.

Hypertension may be present in persons with any form of NS.

o The ISKDC studies revealed that approximately 30% of patients with MCNS have systolic and diastolic pressures greater than the 90th percentile for age.

o If values greater than the 98th percentile were used to denote an abnormality, then approximately 20% had systolic pressures, and approximately 13% had diastolic pressures that were elevated.

o The percentage of children with hypertension is higher in those with FSGS and, particularly so, in patients with MPGN in whom hypertension may be severe.

Other consistent abnormalities of the physical state are unusual and only a few are mentioned.

o Signs of a concurrent upper RTI may be present, and some children have overt evidence of an atopic state with varying degrees of eczema.

o An occasional child demonstrates evidence of an insect sting and/or bite.

o Abdominal tenderness is unusual in the absence of a peritoneal infection.

On rare occasions, the child with nephrosis may demonstrate signs of either arterial or venous thrombosis, secondary to a hypercoagulable state.

o The thrombosis may involve peripheral or internal vessels.

o Early recognition is essential if the involved organ is to be saved.

Causes:

Edema, the predominant clinical feature, ultimately is the result of the urinary loss of large amounts of albumin from the serum with a consequent lowering of the serum albumin concentration.

o The cause for the maintenance and progression of the edema is less certain (see Pathophysiology).

o The GFR often is reduced by a mild-to-moderate degree, and the ability of the renal tubules to aggressively reabsorb sodium and water is enhanced. Oliguria and edema ensue.

o The edema first collects in those sites where tissue resistance is low, such as the periorbital area and in the scrotum.

o Later, the edema becomes generalized.

The etiology of the hypertension probably is multifactorial.

o In some patients with elevated blood pressure (BP), particularly in small children with MCNS, the PV is low, and the associated tachycardia suggests an increase in sympathetic nervous system activity. In such patients, the BP falls following an infusion of albumin.

o In most older patients with NS, the PV is either normal or increased. In some of these patients, BP returns to normal with diuresis.

o Plasma renin levels have been reported variously as either normal or slightly increased; however, the response to blockade of the renin-angiotensin system does not support this as the primary cause of the hypertension.

o Various cytokines known to have pressor effects are increased and may be the primary cause of hypertension.

DIFFERENTIALS

Acute Poststreptococcal Glomerulonephritis Angioedema Heart Failure, Congestive Nephritis Nephrotic Syndrome Obesity Oliguria Protein-Losing Enteropathy Proteinuria Systemic Lupus Erythematosus

Other Problems to be Considered:

GlomerulonephritisLupus erythematosus in infants and children

A differential diagnosis is a 2-step process. First, question what other conditions are likely to present similarly (eg, edema). Allergic reactions probably are the most common ones: it is striking how often the child with new-onset nephrosis initially is believed to have periorbital edema as a result of an allergic reaction. Other conditions that may produce facial or generalized edema in children include congestive heart failure, severe hepatic disease associated with hypoalbuminemia, protein-losing enteropathy (cystic fibrosis, particularly), and congenital defects in albumin synthesis. After the urine is obtained and it is recognized that proteinuria is associated with the edema, the possibility of nephrotic syndrome is suspected. One must then consider the various types of glomerular disease that may produce this combination.

Chronic liver disease with cirrhosis

Lab Studies:

The key to determining that renal disease is responsible for the initial clinical presentation is an examination of the urine for protein and cellular elements. Most patients with MCNS have proteinuria without hematuria, but the presence of microhematuria does not eliminate this diagnosis from consideration. The proteinuria predominately is selective with a high ratio of urinary albumin to globulin (UA/G). In patients with FSGS, proteinuria is less selective but still more so than in patients with MPGN. In individuals with MPGN, hematuria routinely is present. Although measurements of protein selectivity are not performed routinely in the United States, clinical studies from Europe confirm the utility of this test.

The magnitude of proteinuria varies with the state of disease activity and with the histologic abnormality.

o The amount of protein in a random urine sample of a patient with NS usually exceeds 100 mg/dL, and values as high as 1000 mg/L are common. Protein-to-creatinine ratios (normal <0.2) may vary from 1 to 10, suggesting 24-hour protein excretions of 1-10 g.

o According to the ISKDC definitions, the lowest amount of urinary protein consistent with the diagnosis of NS is 40 mg/m2/h or approximately 1000 mg/m2/d.

o Patients with MCNS and MN usually excrete larger amounts of protein than patients with other histologic subtypes. However, MN is rare in children.

o The major protein excreted in any form of NS is albumin, but the UA/G ratio in excreted urine is influenced greatly by the histologic subtype.

Hematuria may be present, and its frequency depends on the subtype of NS.

o Microscopic hematuria is present at the onset of the disease in 20-30% of patients with MCNS, but it disappears thereafter. By contrast, microscopic hematuria is consistently present in 80-100% of patients with MPGN and in 60% of patients with MN.

o Patients with FSGS have hematuria more often than patients with MCNS, but the presence of hematuria cannot be used to distinguish between the 2 conditions.

o Although unusual in persons with MCNS, macroscopic hematuria has been reported.

Hypoalbuminemia is the second of the cardinal laboratory features of NS, whatever the histopathologic subtype.

o The concentration of serum albumin compatible with NS is less than 2.5 g/dL. o The serum concentration of albumin is correlated indirectly with the magnitude of

proteinuria; thus, patients with MCNS, in general, have lower concentrations than those with other forms of NS.

o Values as low as 0.5 g/dL are not uncommon.

Hyperlipidemia is a common feature of NS and, in general, correlates inversely with the concentrations of serum albumin.

o The low-density lipoprotein and very-low-density lipoprotein cholesterol concentrations are elevated, whereas the high-density lipoprotein cholesterol level is decreased.

o Values for lipids may remain moderately elevated for as many as 1-3 months after complete remission of proteinuria.

Renal function is normal in most children at onset of NS.

o However, some patients with MCNS may have a mild-to-moderate reduction of GFR, possibly due to the decrease in effective blood volume; the values usually return to normal as diuresis occurs.

o Marked reductions in renal function reflected in a persistent elevation of serum creatinine indicate a histologic subtype other than MCNS.

Other lab study results are as follows:

o Elevated values of hemoglobin and hematocrit are common when the patient has marked hypoalbuminemia, and these elevated values are caused by the contracted PV.

o Elevated WBC counts occasionally are observed, even in the absence of infections.

o Hyponatremia is factitious: the amount of water (in which sodium is dissolved) per unit of serum volume is reduced, due to hyperlipidemia. The occurrence of this pseudohyponatremia is declining with the routine use of ion selective instruments to measure the serum sodium concentration

o Hypocalcemia (low total serum calcium) is common in patients with active NS due to hypoalbuminemia; however, the ionized serum calcium is usually within reference range.

o Serum complement levels are within reference range, except in patients with MPGN.

Imaging Studies:

No routine imaging studies are indicated in patients with NS.

On chest radiographs, pleural effusions are not uncommon and their presence correlates directly with the degree of edema and indirectly with the serum albumin concentration. Ascites is common.

Renal ultrasonography usually reveals normal to slightly enlarged kidneys with normal echogenicity. Patients with MPGN often demonstrate larger than normal renal shadows with increased echogenicity.

Procedures:

A renal biopsy usually is not performed until after a therapeutic trial of glucocorticoids has proved to be unsuccessful. Exceptions to this general rule may be made in the following situations:

o A child older than 10 years at onset of NS

o Coexistence of significant hematuria, hypertension, and azotemia at the onset of NS

o Any child in whom the levels of serum complement (or C3) are depressed

Histologic Findings: The histologic findings on renal biopsy tissue vary with the subtype of NS.

In MCNS the morphology, by LM examination, is not different from normal. The immunofluorescence results are negative, and no deposits are observed on electron microscopy (EM). The only significant change observed on EM examination is fusion of the epithelial cell podocytes.

Focal global glomerulosclerosis describes, as the name indicates, the presence of a few completely sclerosed glomeruli, with the other glomeruli normal. The meaning of such a lesion is not certain, because of the normally occurring glomerular attrition. For this reason, focal global glomerulosclerosis is considered significant only if more than 5% of the glomeruli are sclerosed globally.

In FSGS, the sclerosis or hyalinosis affects only part of the glomerular tuft of only some of the glomeruli; the remaining glomeruli are normal. Because this lesion is focal and often confined to the juxtamedullary nephrons, it may be missed on renal biopsy examination. Immunofluorescent microscopy yields a variable picture. In some patients all classes of immunoglobulins and complement appear to be trapped in the sclerotic area; in others, distinct immune-complex-type deposits are found, particularly IgM. In children with NS, 7-10% have this lesion at onset, and the lesions of 70-80% of such individuals fail to respond to standard steroid therapy. Clinically, the disease presents in a fashion indistinguishable from MCNS. Two clinical forms of FSGS may exist, one that is observed early in patients whose conditions are not responsive to steroids and another that occurs late during the course of the disease in patients with long records of response to steroid therapy. The FSGS that is observed early more often is associated with early renal failure.

Mesangial proliferative glomerulonephritis (MPN) only recently has been distinguished from MCNS, and some examples of MCNS with mesangial alterations may be inappropriate. LM reveals minimal-to-moderate proliferation of the mesangial cells, with some mesangial expansion; however, the most striking change is observed with

immunofluorescent microscopy, in which IgM, immunoglobulin G, and C3 often are observed.

MPGN occurs in approximately 8% of new unselected children with NS, and in more than 95% of these patients, symptoms are unresponsive to standard steroid regimens. The histopathologic findings are distinct, and all glomeruli are involved. At least 2 varieties of MPGN can be described, both with proliferation of cells and extensive immune deposits as demonstrated by immunofluorescent microscopy and EM.

MGN accounts for only 1-2% of childhood NS. With well-developed lesions, findings on LM examination are typical, but detection of early lesions requires the detail afforded by immunofluorescent microscopy and EM.

Other lesions, including proliferative glomerulonephritis (GN) and chronic GN, occur in approximately 5% of children with NS, but their clinical presentations usually are so different from that of MCNS that they are distinguished easily. The histologic picture varies with the specific etiology.

TREATMENT

Medical Care: The following discussion is confined to the initial treatment of MCNS. Both specific (steroids) and nonspecific treatments (eg, diet, diuretics, antihypertensives) are considered. Treatment of patients whose symptoms do not respond to steroids and those who relapse is discussed in Prognosis.

Specific therapy

o Initial Glucocorticoid (steroid) therapy has changed the morbidity and mortality

of NS and is considered standard. After contraindications to the use of high-dose glucocorticoid drugs are eliminated (ie, active infection), oral prednisone or prednisolone is started in a dose of 2 mg/kg/d (60 mg/m2/d).

The total daily dose is usually divided into 2-3 doses and administered daily for 4-6 weeks. Approximately 90% of patients with MCNS respond to this therapy with complete clearing of proteinuria; however, approximately 20% of children with FSGS and 7% of those with MPGN experience a clinical remission (defined as a diuresis without complete clearing of proteinuria). Most children with MCNS experience response at day 10-14 of such therapy, but a full 6 weeks of daily therapy still is recommended. While higher dosages or longer courses of daily steroids do not significantly change the response rate in persons with MCNS, they do increase steroid toxicity.

Refer children with unresponsive symptoms (ie, with complete clearing of proteinuria) to a pediatric nephrologist for a percutaneous renal biopsy and consideration of an alternative plan of treatment.

o Maintenance: Following the 6 weeks of daily therapy, the standard recommendation is for the dose (of either prednisone or prednisolone) to be reduced to approximately 1.5 mg/kg/d (40 mg/m2/d) administered as a single dose every other morning for an additional 4- to 6-week period. This author believes that such a brief period of maintenance therapy is associated with a higher rate of early recurrence than that observed in patients in whom the maintenance therapy is continued for 3-6 months. Thus, the author's recommendation, which is not based on a controlled study, is as follows:

First 4 weeks - Intensive daily treatment - as above Next 8 weeks - 1.5 mg/kg/d (once per day, every other morning) Second 8-week period - 1 mg/kg/d (once per day, every other morning)

Third 8-week period - 0.5 mg/kg/d (once per day, every other morning) After 29 weeks - Therapy stopped

Nonspecific therapy

o Infection: The child who is nephrotic is a prime candidate for infection. When present, infection has the potential for dissemination, particularly during steroid administration. Thus, closely examine children with NS when febrile, and perform appropriate laboratory studies without delay. If the child is from an environment conducive to tuberculosis, perform a purified protein derivative (PPD) skin test. If found to be positive for tuberculosis, the child should be investigated and treated appropriately. To help prevent various infections, the child should be in relative reverse isolation to minimize exposure to infectious diseases. This is particularly true during periods of intensive therapy. Documented infections should be treated aggressively, but prophylactic therapy is not indicated. Because of the propensity of nephrotic children for pneumococcal infections, vaccination is indicated after remission is induced.

o Diet: Children with active NS have the tendency to retain sodium. Therefore, a diet low in sodium is indicated. Limitation of fluid intake is unnecessary unless the child's thirst is so stimulated that intake is excessive. The remainder of the diet should be normal. Alterations in protein intake are not indicated.

o Diuretic therapy: Diuretic therapy may be beneficial, particularly in children with symptomatic edema. The loop diuretics (eg, furosemide) administered orally in usual amounts (approximately 1-2 mg/kg/d) are safe and moderately effective. Administer loop diuretics with care because PV contraction already may be present, and further sodium and fluid loss may result in hypovolemic shock. Simultaneous infusion of salt-poor albumin (usually at 1 g/kg body weight administered IV over 1-2 h) enhances the diuretic response. Diuretics other than the loop diuretics (eg, thiazides, spironolactone, metolazone) generally are not potent enough alone to effect diuresis but may have an added effect when combined with furosemide. Metolazone (with or without spironolactone) may be beneficial in combination with furosemide for resistant edema. Carefully monitor patients on this regimen because of the high risk of volume depletion.

o Antihypertensive therapy: Hypertension rarely is observed in patients with MCNS. When present, the hypertension may respond to diuretics; however, just as often, such therapy can be ineffective or even can increase BP, presumably by further reducing renal perfusion and thus enhancing the production of renin. Both angiotensin-converting enzyme inhibitors and calcium channel-blocking agents have been used effectively in such patients.

Deterrence/Prevention:

Although no proven method exists, limiting the occurrence of relapses is desirable. Many relapses occur following respiratory illnesses. Thus, an attempt to limit exposure to subjects with RTIs may be beneficial.

Exacerbations of NS also appear to occur following routine immunizations. Delaying routine immunizations until the child is in remission and off medications for approximately 6 months is desirable.

Complications:

Glomerular lesion

o The rate of complications observed is related directly to the subtype of glomerular lesion; thus, patients whose NS is secondary to MCNS have few complications, while those with FSGS, MPGN, and MGN experience high rates of complications.

o Acute renal failure has been noted in individuals with all types of NS but is rare in persons with MCNS.

o Tubulointerstitial nephritis is unusual in individuals with MCNS and common in persons with other histologic subtypes.

o In some patients with NS, tubulointerstitial involvement is associated with glucosuria and aminoaciduria. The presence of these urinary findings suggests the possibility that FSGS is the underlying cause of the nephrotic syndrome.

o Hypertension is a frequent consequence of MPGN and FSGS.

o Progression to CRF is uncommon in individuals with MCNS; however, CRF is observed with increasing frequency in persons with MGN, FSGS, and MPGN.

Hypoproteinemia

o The massive loss of urinary protein induces a degree of protein malnutrition in all children with NS; children with NS that fails to respond to therapy and are constantly in a negative protein balance are at greater risk of growth failure and other aspects of malnutrition.

o Hyperlipidemia is the direct result of increased hepatic production of lipids and lipoproteins and is related to the degree and duration of the hypoproteinemia. Hyperlipidemia rarely is of major consequence in patients with MCNS; however, in patients whose condition does not respond to therapy or who have one of the other histologic subtypes, chronic hyperlipidemia may become a major health risk of cardiovascular complications. A role for hyperlipidemia in the progression of the renal disease also has been postulated.

o The low serum protein concentrations are not solely due to albuminuria. Even in patients with selective proteinuria, other small molecular weight anionic proteins are lost in the urine, and serum levels are depleted. Some of these proteins (eg, transferrin) are important for transport of other substances (eg, iron), and consequences may ensue. The loss of opsonins appears responsible for the increased propensity for peritonitis. A loss of some of the anticoagulant proteins may be responsible, at least in part, for the increased tendency for thrombosis, either venous or arterial.

Drug therapy

o The primary treatment medication, prednisone or prednisolone, has a very broad range of significant adverse effects. The rate of complications observed with these steroids depends on the dosages used, the frequency of dosing, and the duration of such treatment.

o Mild-to-moderate symptoms (eg, behavioral changes, increased appetite) and cushingoidlike signs (eg, moon facies, truncal obesity, hirsutism) are common during the first 6 weeks of daily therapy but usually begin to subside during the maintenance therapy period and, if steroids are discontinued successfully, usually disappear completely within 3-6 months.

o If longer periods of steroid therapy are required, the risk of complications increases. In addition to an exaggeration of those mentioned above, the complications are more serious neurobehavioral changes (including mild psychoses), obesity, growth arrest, osteopenia, osteoporosis, cataracts, hypertension, hyperglycemia, nephrolithiasis, hyperlipidemia, and others. Incidence of these complications increases greatly with repeated episodes of daily steroid administration.

o If steroids must be used for long periods of time, limit the periods of daily steroid administration.

o While the administration of alternate morning steroids does not remove the risk of such complications, it does lower the risk.

o All of the other drugs used for the treatment of NS (eg, diuretics, antihypertensive agents, immunosuppressive agents such as cyclophosphamide, chlorambucil, cyclosporine) have significant individual toxicities. Carefully assess their benefit-to-risk ratios.

Prognosis:

The prognosis for NS in children depends on the renal histologic findings, and, in large measure, the expected outcome determines the optimal plan of follow-up care. The discussion below focuses primarily on the prognosis for children with MCNS, which is the histologic subtype that accounts for 80% of NS in children.

Patients whose symptoms initially do not respond to prednisone: Complete unresponsiveness to steroids (with persistence of proteinuria and edema) or partial unresponsiveness (persistence of proteinuria following diuresis and resolution of edema) occurs in approximately 8% of children with MCNS.

o On LM examination, the kidneys of such children do not appear different from the kidneys of children whose symptoms initially respond to steroids. However, many of the patients without steroidal response have IgM in the mesangial area, and this may constitute a different subgroup. Some of these children also may have unrecognized FSGS.

o The few patients with MCNS who are still proteinuric after 6 weeks of daily prednisone therapy ultimately respond during the period of alternate-day prednisone therapy or if alternate-day therapy is continued beyond 6 weeks.

o Seriously consider a diagnosis of FSGS in children who remain nephrotic after a standard course of prednisone therapy (eg, 6 wk daily and 6 wk of alternate-day prednisone in prescribed doses). In such patients, consider therapy with an alkylating agent, such as cyclophosphamide, chlorambucil, or nitrogen mustard.

Controlled studies by the ISKDC demonstrated that cyclophosphamide significantly reduces morbidity by shortening the interval between beginning therapy and time of response when compared to continued alternate-day prednisone alone.

Other studies by the same group have demonstrated the ineffectiveness of azathioprine in shortening this response interval.

Anecdotal reports have documented a response to other alkylating agents as well as to cyclosporine A.

Renal biopsy usually is indicated in such patients.

Steroid responders: Approximately 92% of children with MCNS have a full response (disappearance of proteinuria) to a standard course of steroids. Thereafter, the course of the patients varies considerably. They can be divided arbitrarily into the following 3 groups:

o Nonrelapsers: Patients in this category account for approximately 30% (range of 20-50%) of children with MCNS whose symptoms initially respond to steroids. Detailed analyses of various characteristics of NS and the initial therapeutic regimen have not demonstrated conclusive differences between these children and those who relapse. Thus, these patients are assumed to be cured of their disease.

o Infrequent relapsers: The criteria for inclusion in this group are defined in different ways by various investigators, and this accounts for the marked differences in incidence (20-50% of patients with MCNS). Generally, the first relapse occurs after a remission of 3 months or more, and the number of relapses does not exceed 3 per year. Relapses frequently are associated with a respiratory illness (eg, infection, allergy). The relapses tend to respond promptly (10-14 d) to steroids. The prognosis for permanent remission is good, and the progression to steroid resistance, renal failure, or both is negligible.

Institute therapy promptly, after 2-3 days for children who suddenly develop significant proteinuria (2+ or more by dipstick), to prevent development of edema.

Administer prednisone (2 mg/kg/d or 60 mg/m2/d in 3 divided doses) until proteinuria has resolved for 3 days; then administer prednisone on alternate mornings (1.5 mg/kg/d as a single dose) for 6 weeks.

A tapering schedule may be effective at times.o Frequent relapsers: These patients present a potentially serious problem, not so

much from progression of the renal disease but from the adverse effects of prolonged steroid therapy; even maintenance prednisone (alternate-day or other forms) has adverse effects. Increasing numbers of children with prolonged maintenance steroid regimens ultimately have exhibited growth failure, cataracts, osteoporosis, hyperglycemia, behavioral disturbances, and gastrointestinal symptoms.These complications are compounded when, in addition to prolonged maintenance therapy, the child must receive multiple courses of daily steroids because of frequent symptomatic recurrences. In these children, the initial relapse usually occurs within the first 3 months after initial response and frequently occurs within the first few weeks; the relapses may or be associated with a respiratory illness, and they may occur at a frequency of more than 3 per year.Symptoms of some such individuals subsequently fail to respond to steroids. In this author's experience, mesangial deposits of IgM are more likely to be found in these children than in the other groups. Patients who frequently relapse have been reported to account for 25-50% of children with MCNS, with an approximate median figure of 35%.

Cyclophosphamide, chlorambucil, nitrogen mustard, and cyclosporine A sometimes are effective in the treatment of these children. When cyclophosphamide was used in a controlled trial in children who relapsed frequently, more than 50% were still in remission (and receiving no therapy) 2-3 years later. Even in children who do not achieve long-term remission, such therapy tends to increase the intervals between exacerbations and increase sensitivity to prednisone therapy. Unfortunately, as many as 20% of children derive little or no benefit from this therapy.

The potential for long-term consequences from cytotoxic therapy (eg, sterility, teratogenesis) is real and must be weighed against the desirable effects. A number of recent reports proclaim the advantages of cyclosporine in this group of children.

Currently, cyclosporine may be the second-most common specific agent used in the treatment of persons with NS. Some patients whose conditions initially respond to cyclosporine ultimately develop a dependency on continued cyclosporine use. Many of the children whose symptoms initially respond to cyclosporine relapse immediately after the drug is discontinued; some do not respond to renewed therapy.

If cytotoxic therapy is ineffective in prolonging remission or if a child in remission returns to a frequently relapsing course, the alternatives are limited and not very effective. If the child's remission can be maintained with alternate-day administration of steroids and if adverse effects are negligible, then this is the appropriate course. Bolus doses of methylprednisolone, administered intermittently, have had some success. If steroid toxicity becomes a factor, the most appropriate treatment may be cyclosporine A until the steroid toxicity subsides.

A renal biopsy to check for signs of cyclosporine toxicity is indicated at early intervals.

Nonsteroidal anti-inflammatory agents may be used to decrease proteinuria.

o Initial and late nonresponders: Most of these patients either have FSGS that is not evident on the renal biopsy sample or subsequently develop FSGS. Although likely, the evolution of MCNS to FSGS has not been documented definitively.

BIBLIOGRAPHY

Ahmad H, Tejani A: Predictive Value of Repeat Renal Biopsies in Children with Nephrotic Syndrome. Nephron 2000 Apr; 84(4): 342-346.

Bagga A, Hari P, Srivastava RN: Prolonged versus standard prednisolone therapy for initial episode of nephrotic syndrome. Pediatr Nephrol 1999 Nov; 13(9): 824-7[Medline].

Boute N, Gribouval O, Roselli S: NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 2000 Apr; 24(4): 349-54[Medline].

Constantinescu AR, Shah HB, Foote EF: Predicting first-year relapses in children with nephrotic syndrome. Pediatrics 2000 Mar; 105(3 Pt 1): 492-5[Medline].

Eddy AA, Schnaper HW: The nephrotic syndrome: from the simple to the complex. Semin Nephrol 1998 May; 18(3): 304-16[Medline].

Gulati S, Sharma AP, Sharma RK: Changing trends of histopathology in childhood nephrotic syndrome. Am J Kidney Dis 1999 Oct; 34(4): 646-50[Medline].

International Study of Kidney Disease in Children: Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome. Report of the International Study of Kidney Disease in Children. Lancet 1974 Aug 24; 2(7878): 423-7[Medline].

International Study of Kidney Disease in Children: Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int 1981 Dec; 20(6): 765-71[Medline].

International Study of Kidney Disease in Children: The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. A report of the International Study of Kidney Disease in Children. J Pediatr 1981 Apr; 98(4): 561-4[Medline].

Kaplan JM, Kim SH, North KN: Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000 Mar; 24(3): 251-6[Medline].

Kestila M, Lenkkkeri U, Mannikko M et al: Positionally cloned gene for a novel glomerular prtein - nephrin - is mutated in congenital nephrotic syndrome. Moll Cell 1998; 4: 575-582.

Glomerulonephritis (GN)

Background: Bright initially described acute glomerulonephritis (GN) in 1927. Acute poststreptococcal glomerulonephritis (PSGN) is the archetype of acute GN. Acute nephritic syndrome is the most serious and potentially devastating form of various renal syndromes. Acute GN is characterized by the abrupt onset of hematuria and proteinuria, often accompanied by azotemia (ie, decreased glomerular filtration rate [GFR]) and renal salt and water retention.

Pathophysiology: Acute GN has 2 components: structural changes and functional changes.

Structural changes

Cellular proliferation: This leads to an increase in the number of cells in the glomerular tuft because of the proliferation of endothelial, mesangial, and epithelial cells. The proliferation could be endocapillary (ie, within the confines of the glomerular capillary tufts) or extracapillary (ie, in the Bowman space involving the epithelial cells). In extracapillary proliferation, proliferation of parietal epithelial cells leads to the formation of crescents, a feature characteristic of certain forms of rapidly progressive GN.

Leukocyte proliferation: This is indicated by the presence of neutrophils and monocytes within the glomerular capillary lumen and often accompanies cellular proliferation.

Glomerular basement membrane thickening: This development appears as thickening of capillary walls using light microscopy. Using electron microscopy, this may appear as the result of thickening of basement membrane proper (eg, diabetes) or deposition of electron-dense material, either on the endothelial or epithelial side of the basement membrane.

Hyalinization or sclerosis: These conditions indicate irreversible injury. Electron-dense deposits: Such deposits could be subendothelial, subepithelial,

intramembranous, or mesangial, and they correspond to an area of immune complex deposition.

These structural changes could be focal, diffuse or segmental, and global.

Functional changes

Functional changes include proteinuria, hematuria, reduction in GFR (ie, oligoanuria), and active urine sediment with RBCs and RBC casts. The decreased GFR and avid distal nephron salt and water retention result in expansion of intravascular volume, edema, and, frequently, systemic hypertension.

Poststreptococcal glomerulonephritis [PSGN]

Previously M-protein of the organism was felt to be responsible for PSGN. These studies have been discounted recently. Recently, nephritis-associated streptococcal cationic protease and its zymogen precursor (NAPR) has been identified as a glyceraldehyde-3-phosphate dehydrogenase that functions as a plasmin(ogen) receptor. This binds to plasmin and activates complement via alternate pathway. Antibody levels to NAPR are elevated in streptococcal infections (of group A,C

and G) associated with glomerulonephritis, but are not elevated in streptococcal infections without glomerulonephritis, where as anti-streptolysin-O titers are elevated in both circumstances. These antibodies to NAPR persist for years and perhaps are protective against further episodes of PSGN.

Frequency:

In the US: GN comprises 25-30% of all cases of end-stage renal disease (ESRD). About one fourth of affected patients present with acute nephritis syndrome. Most cases that progress do so relatively quickly, and end-stage renal failure may occur within weeks or months of acute nephritic syndrome onset. Asymptomatic episodes of PSGN exceed symptomatic episodes by a ratio of 3-4:1.

Internationally: Geographic and seasonal variations in the prevalence of PSGN are more marked for pharyngeally associated GN than for cutaneously associated disease.

Race: Postinfectious GN has no predilection for any racial or ethnic group. A higher incidence (related to poor hygiene) may be observed in some socioeconomic groups.

Sex: Acute GN predominantly affects males (ie, 2:1 male-to-female ratio).

Age: Postinfectious GN can occur at any age but usually develops in children. Outbreaks of PSGN are common in children aged 6-10 years.

History: Taking a proper history is important and helpful.

Determine onset of disease: Ask the patient about onset and duration of illness.

Identify a possible etiologic agent (eg, streptococcal throat infection [pharyngitis], skin infection [pyoderma]): Recent fever, sore throat, joint pains, hepatitis, travel, valve replacement, and/or intravenous drug use may be causative factors. Rheumatic fever rarely coexists with acute PSGN.

Identify systemic disease (eg, arthralgia, diabetes).

Assess the consequences of the disease process (eg, uremic symptoms): Inquire about loss of appetite, generalized itching, tiredness, listlessness, nausea, easy bruising, nose bleeds, facial swelling, leg edema, and shortness of breath.

Identify clinical features: Inquire about edema, decreased volume and frequency of urination, systemic hypertension, uremic symptoms, costovertebral tenderness (ie, enlarged kidneys [rare]), and gross hematuria. Gross hematuria is the most common abnormality observed in patients with acute PSGN and often manifests as smoky-, coffee-, or cola-colored urine.

Physical:

Signs of fluid overload

o Periorbital and/or pedal edema

o Edema and hypertension due to fluid overload - In 75% of patients

o Crackles (ie, if pulmonary edema)

o Elevated jugular venous pressure

o Ascites and pleural effusion (possible)

Rash (ie, vasculitis, Henoch-Schönlein purpura)

Pallor

Renal angle (ie, costovertebral) fullness or tenderness, joint swelling, or tenderness

Causes: The causal factors that underlie this syndrome can be broadly divided into infectious and noninfectious groups.

Infectious

o Streptococcal: Poststreptococcal GN usually develops 1-3 weeks following acute infection with specific nephritogenic strains of group A beta-hemolytic streptococcus. The incidence of GN is approximately 5-10% in persons with pharyngitis and 25% in those with skin infections.

o Nonstreptococcal postinfectious glomerulonephritis Bacterial - Infective endocarditis, shunt nephritis, sepsis, pneumococcal

pneumonia, typhoid, secondary syphilis, meningococcemia, and infection with methicillin-resistant Staphylococcus aureus (MRSA)

Viral - Hepatitis B, infectious mononucleosis, mumps, measles, varicella, vaccinia, echovirus, parvovirus, and coxsackievirus

Parasitic - Malaria, toxoplasmosis

Noninfectious

o Multisystem systemic diseases - Systemic lupus erythematosus, vasculitis, Henoch-Schönlein purpura, Goodpasture syndrome, Wegener granulomatosis

o Primary glomerular diseases - Membranoproliferative GN (MPGN), Berger disease (ie, immunoglobulin A [IgA] nephropathy), "pure" mesangial proliferative GN

o Miscellaneous - Guillain-Barré syndrome, radiation of Wilms tumor, diphtheria-pertussis-tetanus vaccine, serum sickness

o Miscellaneous - Guillain-Barré syndrome, radiation of Wilms tumor, diphtheria-pertussis-tetanus vaccine, serum sickness

Differential

Glomerulonephritis, Crescentic Glomerulonephritis, Diffuse Proliferative Glomerulonephritis, Membranoproliferative Glomerulonephritis, Poststreptococcal

Glomerulonephritis, Rapidly Progressive Goodpasture Syndrome Hemolytic-Uremic Syndrome Nephritis, Interstitial Nephritis, Lupus

Other Problems to be Considered:

Postinfectious GN must be differentiated from the following conditions:

o IgA nephritis: The latent period between infection and onset of nephritis is 1- 2 days, or it may be concomitant with upper respiratory tract infection (ie, "synpharyngitic" in contrast to 1-3 wk "postpharyngitic nephritis" in PSGN).

o MPGN (type I, type II): This is a chronic disease, but it can manifest with an acute nephritic picture with hypocomplementemia; failure of acute nephritis to resolve should prompt consideration of this possibility.

o Lupus nephritis: Gross hematuria is unusual in lupus nephritis.o GN of chronic infection: This can manifest as acute nephritis. Unlike PSGN, in

which the infection may have resolved by the time nephritis occurs, patients with nephritis of chronic infection have an active infection at the time nephritis becomes evident. Circulating immune complexes play an important role in the pathogenesis of acute GN in these diseases.

o Vasculitis: Nephritis of MRSA may have vasculitic lesions of the lower extremities.

o Predominantly nonglomerular diseases: Thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, atheroembolic renal disease, and acute hypersensitivity interstitial nephritis may present with features of acute nephritic syndrome and should be differentiated

Lab Studies:

Urinalysis and sediment examination

o These tests are crucial in the evaluation of patients with acute nephritic syndrome.

o Look for protein, blood, RBCs and WBCs, dysmorphic red cells, acanthocytes, cellular (ie, RBC, WBC) casts, granular casts, and oval fat bodies. In some instances, marked sterile pyuria is present.

o Finding RBC casts is an almost pathognomonic sign of GN.

o Urine electrolytes, urine sodium, and fractional excretion of sodium (FENa) assays are needed to assess salt avidity.

Blood, urea, and nitrogen (BUN); serum creatinine; and serum electrolytes (especially serum potassium level)

Complete blood cell count

Erythrocyte sedimentation rate

Complement levels (C3, C4, CH50)

o Low C3 levels are found in almost all patients with acute poststreptococcal nephritis; C4 levels may be slightly low.

o Type III cryoglobulinemia may be present.

Twenty-four–hour urine test for total protein and creatinine clearance: Remember that creatinine clearance is a "steady-state" measurement. The creatinine clearance may not reveal the true picture because of rapidly changing renal function; therefore, it is better to wait until renal function has stabilized before performing creatinine clearance.

Antistreptolysin-O titer (ASOT) or streptozyme titer: Increasing titer levels confirm recent infection. In patients with skin infection, anti-DNase B titers are more sensitive than ASOT for infection with Streptococcus.

Antibody to NAPR: Levels are elevated in streptococcal infections with GN but not in streptococcal infections without GN.

If MRSA is the inciting agent, then hypocomplementemia is usually not present, but plasma immunoglobulins, especially IgA, are markedly elevated.

Qualitative estimation of proteinuria: Determination of high-molecular weight (HMW) protein, like fractional excretion of IgG (FEIgG), and low-molecular weight (LMW) protein, like alpha-1-microglobulin, may help predict the clinical outcome and may help in guiding steroid and immunosuppressive therapy, especially in patients with primary glomerular diseases with nephrotic syndrome.

Imaging Studies:

Abdominal ultrasound

o Assesses renal size

o Assesses echogenicity of renal cortex

o Excludes obstruction

Procedures:

Generally, a renal biopsy is not necessary for diagnosis of acute PSGN; however, in most cases, it is important because histology guides both prognosis and therapy.

Histologic Findings: Diffuse endocapillary proliferative changes are found (see Images 1-2). In postinfectious GN, the glomerulus is hypercellular with marked cellular infiltration (ie, polymorphonuclear neutrophils, monocytes). Immunofluorescence may show fine granular deposits of immunoglobulin G in a "starry sky” appearance (see Image 3). Large subepithelial deposits may be observed on electron microscopy (see Image 4). Crescents may be observed

Medical Care: Treatment of acute PSGN is mainly supportive because there is no specific therapy for renal disease. Treat the underlying infections when acute GN is associated with chronic infections.

Antimicrobial therapy

o Antibiotics (eg, penicillin) are used to control local symptoms and to prevent spread of infection to close contacts.

o Antimicrobial therapy does not appear to prevent the development of GN, except if given within the first 36 hours.

Loop diuretic therapy

o Loop diuretics may be required in patients who are edematous and hypertensive in order to remove excess fluid and to correct hypertension.

o Relieves edema and controls volume, thereby helping to control volume-related elevation in BP.

o Vasodilator drugs (eg, nitroprusside, nifedipine, hydralazine, diazoxide) may be used if severe hypertension or encephalopathy is present.

o Glucocorticoids and cytotoxic agents are of no value, except in severe cases of PSGN.

Consultations: Nephrologist

Diet:

Sodium and fluid restriction - For treatment of signs and symptoms of fluid retention (eg, edema, pulmonary edema)

Protein restriction for azotemic patients - If no evidence of malnutrition

Activity: Recommend bed rest until signs of glomerular inflammation and circulatory congestion subside. Prolonged inactivity does not benefit in the patient recovery process.

TreatmentDrug Category: Antimicrobials (antibiotics) -- In streptococcal infections, early antibiotic therapy may prevent antibody response to exoenzymes and render throat cultures negative, but may not prevent the development of PSGNPenicillin V (Pen VEE K, V-Cillin K) -- More resistant than penicillin G to hydrolysis by acidic gastric secretions and is absorbed rapidly after oral administration. 250 mg of penicillin V = 400,000 U of penicillinDrug Category: Loop diuretics -- Decrease plasma volume and edema by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BPDrug Category: Vasodilators -- Reduce SVR, which in turn may allow forward flow, improving cardiac outputDrug Category: Calcium channel blockers -- In specialized conducting and automatic cells in the heart, calcium is involved in the generation of the action potential. The calcium channel blockers inhibit movement of calcium ions across the cell membrane, depressing both impulse formation (automaticity) and conduction velocity

Deterrence/Prevention:

Early antibiotic therapy of streptococcal infection (ie, within 36 h of onset) may prevent development of PSGN.

Antibiotic treatment of close contacts of the index case may help prevent development of PSGN.

Complications:

Renal failure (rare)

Pulmonary edema

Generalized anasarca and hypoalbuminemia (secondary to severe proteinuria)

Hypertension

Hypertensive encephalopathy

Prognosis:

Prognosis of acute PSGN is generally excellent in children.

Within a week or so of onset, most patients with PSGN begin to experience spontaneous resolution of fluid retention and hypertension.

C3 levels may normalize within 8 weeks after the first sign of PSGN.

Proteinuria may persist for 6 months and microscopic hematuria for up to 1 year after onset of nephritis.

Eventually, all urinary abnormalities should disappear, hypertension should subside, and renal function should return to normal.

Adults with PSGN, particularly older adults, may have a less favorable prognosis.

Few patients with acute nephritis develop rapidly progressive renal failure.

Nephritis associated with MRSA and chronic infections usually resolves after treatment of the infection.

Immunity to type M protein is type-specific, long-lasting, and protective. Repeated episodes of PSGN are therefore unusual.

Approximately 15% of patients at 3 years and 2% of patients at 7-10 years may have persistent mild proteinuria. Long-term prognosis is not necessarily benign. Some patients may develop hypertension, proteinuria, and renal insufficiency as long as 10-40 years after the initial illness.

BIBLIOGRAPHY

Arze RS, Rashid H, Morley R, et al: Shunt nephritis: report of two cases and review of the literature. Clin Nephrol 1983 Jan; 19(1): 48-53[Medline].

Baldwin DS, Gluck MC, Schacht RG, Gallo G: The long-term course of poststreptococcal glomerulonephritis. Ann Intern Med 1974 Mar; 80(3): 342-58[Medline].

Bazzi C, Petrini C, Rizza V, et al: A modern approach to selectivity of proteinuria and tubulointerstitial damage in nephrotic syndrome. Kidney Int 2000 Oct; 58(4): 1732-41[Medline].

Dodge WF, Spargo BH, Travis LB, et al: Poststreptococcal glomerulonephritis. A prospective study in children. N Engl J Med 1972 Feb 10; 286(6): 273-8[Medline].

Neugarten J, Gallo GR, Baldwin DS: Glomerulonephritis in bacterial endocarditis. Am J Kidney Dis 1984 Mar; 3(5): 371-9[Medline].

Oda T, Yamakami K, Omasu F, et al: Glomerular plasmin-like activity in relation to nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. J Am Soc Nephrol 2005 Jan; 16(1): 247-54[Medline].

Rodriguez-Iturbe B: Epidemic poststreptococcal glomerulonephritis. Kidney Int 1984 Jan; 25(1): 129-36[Medline].

Rodriguez-Iturbe B: Nephritis-associated streptococcal antigens: where are we now?. J Am Soc Nephrol 2004 Jul; 15(7): 1961-2[Medline].

Ronco P, Verroust P, Morel-Maroger L: Viruses and Glomerulonephritis. Nephron 1982; 31(2): 97-102[Medline].

Yoshizawa N, Yamakami K, Fujino M, et al: Nephritis-associated plasmin receptor and acute poststreptococcal glomerulonephritis: characterization of the antigen and associated immune response. J Am Soc Nephrol 2004 Jul; 15(7): 1785-93[Medline].