INTRODUCTION:
The occurrence of nephropathy during a hematology is far from an exceptional event. This type of association recognizes multiple and sometimes associated mechanisms, where the very nature of hematological disorders will occur first. Given the diversity of these hematological diseases, we will focus this review on the renal damage of acute and chronic leukemias mainly of lymphoid origin as well as those of non-Hodgkin’s lymphoma or Hodgkin’s disease. Renal lesions specific to myeloma or Waldenström-type lymphoplasmocytic haemopathy, or to non-malignant haemopathy, particularly related to hemoglobinopathy (sickle cell disease), are described elsewhere. The nature of renal lesions is particularly heterogeneous and, in general, all renal structures are interested in the secondary complications of haemopathy. These disorders may concern the glomerulus in the context of an immunological process, interstitium during infiltration by the leukemic or lymphomatous process, or the tubule in case of metabolic disorder secondary to a tumor lysis syndrome.
Finally other causes of renal insufficiency related to extrinsic factors responsible for obstacle on the excretory ways where the vessels of the kidney can be met. The mode of renal presentation is very variable and will depend on the nature of the renal lesion. As we shall see, renal insufficiency or nephrotic syndrome can be indicative of the haematopathy or appear or evolve in its evolution, complicating singularly its therapeutic management and aggravating the prognosis.
GLOBAL RULARY LESIONS:
The association of glomerular nephropathy with various neoplasias is currently well established. The occurrence of extramembranous glomerulopathy during the course of bronchial or digestive cancers, or the appearance of a nephrotic syndrome with minimal glomerular lesions preceding or accompanying the diagnosis of Hodgkin’s disease are classic examples of this type of association.
The physiopathological hypotheses implicated in the occurrence of glomerular lesions during the evolution of neoplastic diseases are numerous. The presence of complex immune deposits or their formation in situ in the basement membrane of the glomerular capillary and the alteration of the cellular immune response T are most often cited.
In this chapter, we will mainly consider glomerular nephropathy related to lymphoid hemopathy, particularly chronic lymphoma, which are of particular interest to the nephrologist by helping pathophysiological understanding of certain types of nephropathy. These haemopathy are in fact characterized by the production of specific humoral factors (monoclonal immunoglobulins [Ig], cytokines) which constitute a potential etiopathogenic link between haemopathy and renal involvement. Recent improvements in detection and characterization techniques for these circulating and urinary Ig, as well as the improvement of immunofluorescence and electron microscopy study of renal biopsy fragments, have made it possible to better describe the glomerular damage observed during immunoproliferative syndromes such as as chronic lymphocytic leukemia B (LLC B) or lymphomas.
Chronic lymphocytic leukemia:
According to the literature, the association between glomerulopathy and chronic lymphocytic leukemia is relatively rare (about 40 cases reported) despite the relative frequency of this type of leukemia (incidence of 15 cases per million inhabitants) and multiple potential causes of glomerular complication. They can indeed occur theoretically for at least three reasons.
First, during CLL B (95% CLL) characterized by proliferation of a B lymphocyte clone, B cells are not immunologically inert but can differentiate and interact with the immunoregulatory system particularly with T cells and NK cells (natural-killer). In addition, leukemic B cells express, on their cell membranes, one or more heavy chain isotypes associated with a single type of light chain (sIg [surface immunoglobulin]). When these cells are secreting, a monoclonal Ig, sometimes cryoprecipitating, can be detected in the serum.
Secondly, the evolution of the disease is often enamelled with infectious complications due to the decrease of the humoral immune response and to a cellular dysfunction T.
Thirdly, the association with an epithelial tumor is also common. These immunological or infectious manifestations may thus be potentially involved in the various types of glomerulopathy that will be discussed.
Analysis of the observations of the literature:
We have recently reported a sery of 13 cases of glomerulopathy associated with chronic lymphoid hemopathy, 11 of which are B-CLL and two of low-grade non-Hodgkin’s lymphoma (NHL), a disease close to B-CLL. CLL observations associated with glomerulopathy have also been reported in the literature, most commonly as isolated cases. The chronology of the diagnosis of both conditions shows that glomerulopathy frequently reveals hematological disorders. In 21 out of 45 cases, the diagnosis of both conditions is carried out simultaneously. Nephrotic syndrome is present in the majority of cases (85%) associated with renal failure in a third of the observations. Dysproteinemia is also mentioned in about half of the 37 cases where it has been specifically investigated (nine cryoglobulinemias and eight monoclonal gammopathy).
This abnormally high percentage of dysproteinemias (about 50%) contrasts with their low incidence (5 to 10%) usually reported in the CLL sery.
However, the frequency of monoclonal gammopathy during CLL seems higher when sensitive techniques are used.
Histological lesions:
The analysis of glomerular lesions reported in the literature and in our sery shows a predominance of cases of membranoproliferative glomerulonephritis (GNMP) found in 18 cases associated in nine cases with dysproteinemia.Extramembranous glomerulopathy (GEM) is reported in seven patients. One of our patients had an atypical form of GNMP characterized by associated mesangial proliferation and extramembranous monotypic deposition, in the absence of circulating monoclonal component. In electron microscopy, these deposits had a microtubular fibrillar organized structure. We also observed a case of mesangial hypertrophy with exclusive deposits of μ heavy chain and light chain localized in the mesangium and associated with circulating monoclonal IgM.
The other observations reported are more heterogeneous, including three cases of nephrotic syndrome with minimal glomerular lesions, four cases of focal hyalinosis, three cases of extracapillary proliferative glomerulonephritis, one case in the context of severe infectious complications of CLL and one case associated with antibody. anti-cytoplasm of the anti-myeloperoxidase polynuclear, three cases of unclassified proliferative glomerulopathy, two cases of amyloidosis and finally one case of immunotactoid glomerulopathy and fibrillar glomerulopathy. The presence of an interstitial infiltrate of tumor appearance is mentioned in some observations.
Treatment:
Treatment sensitivity is an important feature of glomerular disease of B-CLL. Primary GMPNs and GEMs are usually not improved by the various therapeutic protocols proposed over the past 20 years (corticosteroids, immunosuppressants, etc.). B hemopathy seem to respond remarkably to treatment. Indeed, in nine of the 13 patients in our sery whose monitoring was prolonged, remission of the most commonly completed nephrotic syndrome was observed in seven cases where it was present, and improvement of renal function was noted in seven patients while she remained normal in two other patients. In all cases in the literature, treatment with chlorambucil or cyclophosphamide, with or without corticosteroid therapy, is effective not only on haematological but also renal manifestations.
Complete remission of nephrotic syndrome and / or regression of renal failure occurred in 10 of 13 patients with GNMP and in the five cases of GEM for which treatment was specified. These remissions accompanied the haematological improvement.
This sensitivity to treatment, and more particularly to chlorambucil used as monotherapy in five patients in our sery, is remarkable considering the usual ineffectiveness of this drug in the treatment of primary glomerular nephropathy. This effect suggests that the improvement in renal damage is mainly due to the control of the hematological disease confirming the paraneoplastic character of these nephropathy.
Pathophysiology:
The physiopathological analysis of the cases observed is of great interest because of the exemplary nature of some of them. In a number of cases, a close relationship between lymphoid B proliferation and glomerulopathy may be proposed in the presence of observations of cryoglobulins responsible for GNMP, the most frequent glomerular involvement or monoclonal Ig glomerular deposits with or without a monoclonal component. flowing.
Role of cryoglobulins:
The role of cryoglobulins, frequently found (six cases in our sery and ten in the literature, or 40% of cases) deserves special mention. The existence of a cryoglobulinemia type I or II is not surprising during a lymphoproliferative syndrome such as CLB B clone whose clone may be secreting in a number of cases. In addition, bacterial or viral infections, which are common in this context, can stimulate the formation of type III cryoglobulins. These cryoglobulins can, on the one hand, be considered as immune complexes in which the antigen is a polyclonal Ig (cryoglobulin type II or type III) or remains of undetermined nature (cryoglobulin type I). In the case of cryoglobulin type II or III, polyclonal Ig has an antibody activity most often unidentified.
Gilboa et al reported two interesting observations in patients with CLL associated with type I GNMP, hypocomplementemia, and IgG IgG monoclonal IgG. Cryoglobulin components are found in the kidney and Ig eluted from both kidney and cryoglobulin binds in vitro to patients’ glomeruli and not to normal glomeruli, suggesting that the monoclonal IgG component is directed against antigens. non-glomerular These could be lymphocyte antigens as suggested by Day et al. Some anti-lymphocyte antibody could bind directly to glomerular antigenic targets due to cross-reactivity between lymphocyte antigens and glomerular epithelial cells. Non-lymphocyte antigens could also be involved. Sutherland and Mardiney have identified immune complex deposits containing Oncornavirus antigen in the glomeruli of patients with leukemia or lymphoma; however, this observation having been made in the absence of clinical symptomatology, the pathogenic character of these immune complexes remains uncertain. The hypothesis of anti-idiotypic antibody for the B lymphocyte membrane Ig of CLL was also raised. Finally, the ability of these cryoglobulins to precipitate in the vessels also confers on them a direct pathogenic role, not mediated by immune complexes more particularly suspected in forms of GNMP with intracapillary thrombi and fibrillar organization of deposits in electron microscopy. Whatever the mechanism leading to cryoglobulin deposition, macrophage infiltration appears to be of essential pathogenic importance, and may even precede the detection of immune complexes.
Direct pathogenic role of monoclonal immunoglobulins:
A number of heterogeneous observations of glomerular lesions suggest a direct pathogenic role of monoclonal Ig during CLL, apart from the presence of cryoglobulinemia. In four of our patients, monotypic deposits were detected in the absence of cryoglobulin. In two of them, a circulating monoclonal component was found, while in the other two the monoclonal component was not detected, despite an immunofixation investigation.
In three of these observations, the monoclonal component induced complement activation. These observations make it possible to implicate the direct pathogenic role of the monoclonal component in the absence of cryoprecipitation.Thus mesangial hypertrophy lesions with exclusive deposits of light chains observed in one of our patients evoke the initial stage of a disease of monoclonal Ig deposits (MDIM). Similar observations have been reported in the literature, but the lack of systematic study with light antiserum antisera or makes it difficult to analyze certain observations.Brodowsky reports focal glomerulosclerosis in a patient with Bence-Jones proteinuria. Seney et al reported a more convincing case of MDFIM in a patient with circulating IgG monoclonal Ig associated with Bence-Jones proteinuria and nodular glomerulosclerosis lesions with exclusive immunohistochemical labeling of mesangial nodules by antichain antibody. lightly.
However, other observations are different from MDIM as for two of our patients (an LLC with GEM and a B lymphoma with GNMP). In both cases, histological examination revealed a fibrillar appearance of glomerular deposits in electronics. Touchard also reported two similar observations of atypical GEM in CLL B patients with monotypic IgG extramembranous deposits despite the absence of circulating monoclonal dysglobulinemia sought by immunofixation.At the ultrastructural level, the glomeruli contained organized microtubular structures also detected in the cytoplasm of circulating lymphocytes, suggesting a possible physicochemical anomaly of the monoclonal component leading to its rapid deposition in the glomeruli. Other cases of fibrillar nephropathy have recently been reported in low-grade B-CLL or B-cell lymphoma. The fibrillar appearance of glomerular deposits in electron microscopy, and the absence of tubular deposits distinguish these cases from the disease of Ig deposits. In general, these observations can be classified in the heterogeneous group of fibrillar glomerulonephritis including also immunotactoid glomerulopathy. One of the patients in the Korbet immunotactic glomerulopathy sery also had B-CLL. These glomerulopathy with microtubular organized deposits of monoclonal Ig thus define a new paraneoplastic syndrome associated with B-CLL and low-grade B lymphomas.
These observations of LLC B and B lymphomas characterized by the presence of glomerular deposits of Ig or monoclonal Ig fragments are of great physiopathological interest: they make it possible to establish a link represented by the monoclonal component between the lymphoid proliferation and glomerular involvement; forms without detectable circulating monoclonal Ig suggest the existence of particular Ig abnormality (unusual sensitivity to proteolytic enzymes, secretion in polymeric form, physicochemical anomaly …) similar to those observed in the MDIM; the diversity of observed glomerular lesions widens the spectrum of glomerular damage secondary to lymphoplasmocytic dyscrasias.
Amyloidosis:
Amyloidosis appears to be rare during CLL and is reported in only two previous observations. The character of amyloidosis is not specified and the notion of AA amyloidosis in a patient with hairy cell leukemia does not allow, due to the frequency of monoclonal dysglobulinemias found during CLL, to prejudge the type of amyloidosis. of the other two cases.
Nephrotic syndrome with minimal glomerular lesions (LGM):
Observations of nephrotic syndromes at LGM or associated with hyalinosis during CLB and CLL can shed new light on the pathophysiology of these syndromes. There are abnormality of T cell functions in B-CLLs, particularly concerning an increase in suppressor CD8 T cells. These facts support the hypothesis involving dysregulation of cellular immunity characterized by increased suppressor T activity in the pathogenesis of nephrotic LGM syndromes.
Hairy Cell Leukemia:
The literature mentions five cases of hairy cell leukemia-associated glomerulopathy with a phenotype similar to those of B-cell B. These observations reported two patients with renal amyloidosis, two cases of GNMP including a case with type III cryoglobulinemia and finally a case of glomerulopathy with mesangial IgA deposits.
Non-Hodgkin’s lymphoma:
This term refers to a disparate group of malignant lymphocytic diseases developed mainly from B or T lymphocytes, at different stages of their maturation and whose grouping is essentially justified by the usually tumoral and ganglionic presentation. Although the potential causes of glomerular nephropathy are numerous, as is the case in CLL, the cases most often reported as isolated cases are rare, given the frequency of these conditions in adults, but also in children.
These observations of NHL are distinguished from those of CLL by the lower prevalence of dysproteinemias and by the higher frequency of proliferative glomerulopathy, especially extracapillary glomerulopathy (15/47). It is interesting to note that of the 12 cases of GNMP, eight were described in the context of well-differentiated, low-grade CL-B lymphoblastic lymphoma, with, in six out of eight cases, the presence of dysproteinemia. Cryoglobulinemia type II (five cases of nephrotic syndromes with LGM associated with this type of lymphoma have also been reported.) Finally, if, in the context of lymphoid hemopathy, amyloidosis seems to be the prerogative of Hodgkin’s disease. and lymphoplasmocytic dyscrasias, two recent cases of AL amyloidosis have been reported in low-grade NHL both associated with the production of a monoclonal protein (and IgG).
Glomerular nephropathy observed in T-cell lymphohemopathy and angio-immunoblastic lymphadenopathy are also very heterogeneous. Two cases of T lymphoma have been reported with segmental and focal hyalinosis. Six cases of fungoid mycosis, cutaneous hemopathy of T origin, associated with glomerular nephropathy have been published. In three cases, it was mesangial IgA nephropathy, in a case of a nephrotic syndrome with minimal glomerular lesions with acute interstitial lesions, for which remission was obtained after treatment with interferon α. The last two observations concern a case of glomerulonephritis with immune complexes and a rapidly progressive glomerulonephritis with fibrillar deposits.
Angio-immunoblastic lymphadenopathy, an atypical lymphoid hemopathy that can progress to malignant lymphoma, usually of the T-cell line, may also be associated with heterogeneous glomerular involvement: proliferative lesions with necrotizing angiitis, minimal glomerular lesions or renal nephropathy. IgA.
Burkitt’s lymphoma must be set apart because it is one of the few hematological diseases whose etiology is known because the responsibility for the Epstein-Barr virus is established. Hyman reports a case of type I GNMP with IgG and C3 deposits occurring 4 months after the start of treatment. Remission of the nephrotic syndrome is obtained after treatment with cyclophosphamide. Oldstone showed glomeruli in two patients with Burkitt’s lymphoma, Ig and C3 deposits. IgG eluted from renal biopsy fragments had specificity directed against Epstein-Barr virus. The clinical features of these two patients and the existence of possible renal disease are not specified.
Hodgkin’s disease:
The association between chronic lymphoid hemopathy and glomerular nephropathy is probably the best known with Hodgkin’s disease. However, the incidence of nephrotic syndrome in Hodgkin’s disease remains relatively low, with all retrospective sery approximately 0.5 to 1%. Various reviews of the literature have been devoted to this subject and make it possible to gather about a hundred cases collected up to 1985, which have been added to since, 11 additional observations.
The distribution of the various histological types of glomerular nephropathy during Hodgkin’s disease reveals the predominance of amyloidosis (37% of cases reported) and nephrotic syndromes with LGM or segmental and focal hyalinosis (42% of cases).
Amyloidosis and Hodgkin’s disease:
The observations of renal amyloidosis associated with Hodgkin’s disease were mainly described before 1970, and although several additional cases were reported up to the 1980s, they mainly concerned retrospective study. This decrease in the frequency of amyloidosis observations can be mainly attributed to the effectiveness of modern therapeutic protocols for obtaining rapid remission of the disease preventing the onset of amyloidosis, a late complication of the disease. The nature of amyloidosis has been identified in a small number of cases as AA (amino acid), which is not surprising since it complicates diffuse and advanced forms of the disease and there is no monoclonal Ig production in this hemopathy.
Nephrotic syndrome with minimal glomerular lesions and Hodgkin’s disease:
Forty cases of Hodgkin’s disease associated with nephrotic syndrome secondary to LGM or more rarely to segmental and focal hyalinosis (four cases) has been reported to date in the literature. Several remarks concerning this association deserve to be made.
The nephrotic syndrome usually appears early in the course of the disease, is revealing in 50% of cases and may even precede the diagnosis of several months.
The relapse of the nephrotic syndrome may be contemporary or precede a new outbreak of hematology. The search for proteinuria is therefore one of the essential elements of surveillance for Hodgkin’s disease.
Whether chemotherapeutic, radiotherapy, surgical or mixed, the specific and effective treatment of Hodgkin’s disease allows the complete and rapid remission of the nephrotic syndrome in 100% of cases in a sery, thus arguing for its paraneoplastic nature. Relapses of the nephrotic syndrome are also sensitive to the specific treatment of hematology.
Among the predisposing factors, age, sex or stage of the disease have no particular characteristics. On the other hand, the association with the “mixed cellularity” type of the Rye classification seems more frequent since this histological type is observed in 35% of the cases of Hodgkin’s disease whereas it is noted in 75% of the patients having a nephrotic syndrome.
The pathophysiology of SN at LGM during Hodgkin’s disease remains uncertain and is based on the analogy with idiopathic LGM SN. In both conditions, functional abnormality of suppressor CD8 + T cells are present. This hyperactivity of T suppressors could be responsible for the production of lymphokines acting on the permeability of the glomerular basement membrane. This mechanism has long been evoked as possible origin of lipoid nephrosis without currently any humoral factor of presumed lymphocyte origin has yet been identified with certainty.
Other glomerulopathy associated with Hodgkin’s disease:
Other types of nephropathy have been described in association with Hodgkin’s disease, but with a lower frequency: five GEM observations and two cases of GNMP (in), to which must be added six cases of extracapillary lomerulonephritis associated with the presence of glomerular basal antimembrane antibody. The pathogenesis of this The last association remains obscure and could involve the release and presentation of nephritogenic epitopes of the basement membrane, or an abnormal immune response induced by hematology. Finally, an observation of ascending glomerulonephritis in Wegener’s disease following complete remission of Hodgkin’s disease has also been reported.
Castelman’s disease:
Although it is not a malignant disease stricto sensu, Castleman’s disease is interesting to consider because it illustrates in a remarkable way the concept of paraneoplastic syndrome. This condition, described in 1956, generally associates polyclonal lymphoid proliferation with vascular hyperplasia and affects one or more lymph nodes. The occurrence of Kaposi’s sarcoma or lymphoma during its course is frequent (10 to 20% of cases). Of the 400 to 500 cases reported in the literature, renal involvement is mentioned in 34 patients including 18 amyloid nephropathy (including 16 of type AA) and 10 other glomerular lesions (including five membranoproliferative glomerulonephritis), four thombotic microangiopathy and two acute interstitial nephritis. . In cases where AA amyloidosis occurs in an isolated plasmocytic form, removal of the tumor leads to remission of the nephrotic syndrome and the disappearance of amyloid deposits is formally demonstrated in five cases.
The amyloidogenesis could be induced by the IL (interleukin) 6 secreted by the tumor, and / or by the HHV-8 virus (human herpes virus) whose gene codes for IL6 motifs and which is associated with certain case of Castleman’s disease. This physiopathological hypothesis would also be evoked in the forms of renal involvement involving endothelial proliferation.
INTERSTITIAL LESIONS:
In this chapter, we will consider the direct interstitial lesions related to parenchymal infiltration by hematology where the severity of renal involvement is highly variable, ranging from asymptomatic infiltration to acute renal insufficiency anuric revealing the disease. The autopsy sery analysis revealed the high prevalence of renal infiltration in cases of haemopathy ranging from 33% for acute myoblastic leukemias (n = 585) to 38% for chronic myeloid leukemias (n = 585). = 204) and up to 53 and 63%, respectively, for acute lymphoblastic leukemias (n = 308) and chro- nic lymphocytic leukemias (n = 109). The frequency of autopsic kidney damage during lymphoma is comparable and approximately 50%.
Paradoxically, these frequent histological lesions rarely agree with clinical lesions and renal dysfunction. However, when it is symptomatic, renal infiltration by the leukemic or lymphomatous process is often indicative of the disease and results in severe renal insufficiency associated with a poor or absent urinary syndrome, and kidneys of increased size and inhomogeneous aspect. Renal biopsy most often confirms the diagnosis.
Acute leukemia:
Despite the high frequency of renal interstitial leukemia infiltration in the autopsy sery, the occurrence of acute renal failure related to this infiltration is an exceptional circumstance but very poor prognosis, complicating the management of treatment. A retrospective study reported 16 cases of renal insufficiency secondary to parenchymal infiltration in 1,561 LA cases analyzed corresponding to a prevalence of 1%. All patients had bilateral asymmetrical bilateral nephrometalgia associated with poor or absent urinary syndrome. The treatment was that of leukemia associated in some cases with radiotherapy of renal areas. The evolution of renal function was related to that of leukemia apart from the frequent initial aggravations secondary to a syndrome of tumor lysis.
In contrast, kidney failure is sometimes indicative of LA. Twenty cases published since 1961 and reviewed by Hachicha et al in 1989, should be added at least seven additional cases. These are young patients (21 men and 4 women) corresponding to the usual profile of this type of hemopathy. LA was myeloblastic in 70% of cases and lymphoblastic in 22%. The renal insufficiency is from the start severe with serum creatinine on average equal to 790 mmol / L. Renal imaging shows bilateral nephromegaly. There is diffuse infiltration of renal interstitium by blast cells without glomerular or tubular involvement in the four cases where renal biopsy was performed. The etiology of these renal insufficiency is not always clearly established and probably multifactorial, associating parenchymal infiltration with a functional part linked to digestive disorders or intratubular precipitation of uric acid.
In the absence of prior renal insufficiency and despite the frequency of lysis syndromes, the renal prognosis is good in the long term when the remission of leukemia is obtained.
In a pediatric sery of 68 children in remission of LA, serum creatinine was normal and the mean glomerular filtration rate (GFR) was 110 mL / min / 1.73m2 (70 to 164 mL / min / 1.73m2). 92% of them after 1 to 9 years of follow-up. Six patients (8%) had moderate renal impairment (GFR between 70 and 85 mL / min / 1.73m 2 ), three were hypertensive and four had tubular changes.
Chronic lymphocytic leukemia B:
Despite the high frequency of abnormality observed during autopsy examinations, renal failure is reported in only 1% of patients with CLL, and is usually secondary to an intercurrent complication (infection, dehydration, lysis syndrome, iatrogenic complications). …). Only four cases of renal failure related to leukemic renal infiltration confirmed on histological examination have been reported in the literature. In two cases, the diagnosis of renal failure and CLL was simultaneous, whereas renal involvement was only mentioned after 1 year and 4 years of leukemia progression in the other two cases. The treatment included conventional chemotherapy (cyclophosphamide, vincristine and prednisone) in two cases, allowing the improvement of renal function in the third case, despite a combination of prednisone, chlorambucil and renal irradiation, no improvement is obtained requiring the dialysis treatment until death of the patient.
In the latter case, while chlorambucil alone failed to improve renal function, the addition of prednisone and renal irradiation was followed by a significant improvement in renal function associated with a decrease in renal function. interstitial infiltrate during histological examination.
Lymphomas:
In the autopsy sery of Richmond et al, the prevalence of renal invasion by lymphoma cells is 49% (n = 188). The kidneys are the most common organ after the hematopoietic system, while renal failure is the cause of death in only 0.5% of cases.
Renal insufficiency related to lymphomatous infiltration, either secondary to a multifocal form of lymphoma, or primitive are rare since about fifty cases have been reported in the literature including about thirty since 1981. It is most often lymphoma of high malignancy. The clinic is poor associating an alteration of the general state, digestive disorders and rarely lumbar pains. The urinary syndrome is poor. The kidneys are inhomogeneous and enlarged for imaging, and the diagnosis is almost always made by kidney biopsy. Treatment combining chemotherapy and radiotherapy generally allows a clear improvement in renal function, but the vital prognosis remains mediocre in the medium term.
In about 15 more recently published observations, renal localization appears primitive and isolated despite extensive explorations. The primitive character of renal lymphoma is exemplarily illustrated in the case of a patient with renal lymphoma treated with nephrectomy alone, without chemotherapy or adjuvant radiotherapy, and well with a follow-up of more than 5 years. However, the presence of another location does not exclude primary renal lymphoma, swarming from the kidney can be rapid. Since the kidney is an organ devoid of lymphoid tissue, the origin of these primary renal lymphomas is unclear, and development from the lymphatics of the renal capsule has been suggested. The diagnosis of primary renal lymphoma may be based on a number of criteria: renal failure as initial presentation associated with a high level of lactic dehydrogenase (LDH); uni- or bilateral nephromegaly without obstructive cause; interstitial infiltration with intermediate or high grade lymphoma at the renal biopsy;
the absence or minimal secondary location at the time of diagnosis after evaluation with at least one thoracoabdominal CT scan, osteomedullary biopsy and cerebrospinal fluid examination; improvement of renal function after radiotherapy or chemotherapy. Finally, the CT scan seems more relevant than ultrasound for both diagnosis and evolutionary follow-up.
Cases of renal lymphoma in AIDS patients have also been published. Evolution is rapidly fatal despite appropriate chemotherapy. Despite the scarcity of reported cases, the prevalence of renal lymphoma in populations at risk of AIDS, especially homosexuals, is relatively high at 3 to 13%.
OTHER REAL ATTACKS:
A number of other causes of renal failure are frequently encountered during hemopathy. They concern direct factors related to vascular or ureteral compression phenomena by lymphadenopathy, and tubular disorders secondary to metabolic complications, Ig light chain precipitations and nephrotoxic effects of administered therapy.
Ureteral obstruction:
Ureteral obstruction is one of the most common causes of renal failure seen in lymphoma. Thus, 4% of the 696 patients with malignant lymphoma in the Richmond et al sery have signs of bilateral ureteral obstruction. This frequency is also reported in more recent sery. The obstruction can result from various mechanisms including direct ureters compression by retroperitoneal lymphadenopathy, direct tumor invasion of the ureters or retroperitoneal fibrosis. Each of these processes may be responsible for a ureteropyelocalficial dilation easily demonstrated on ultrasound. The derivation of urine is essential, possibly preceded by high-dose corticosteroid treatment before the specific treatment of lymphoma is implemented.
Invasion of the renal pedicle:
Involvement of the renal pedicle, compression of the renal vessels by lymphadenopathy, may also be responsible for renal failure, arterial hypertension or edema of the lower limbs in case of extension to the vena cava.
Metabolic abnormality:
Metabolic abnormality are often responsible for kidney failure during hemopathy. They may occur in the setting of paraneoplastic syndromes or be linked to tumor lysis either spontaneously or more frequently during the start of chemotherapy or radiotherapy (see below). Hypercalcemia is the most common “spontaneous” metabolic abnormality resulting from stimulation of bone resorption and possibly an increase in renal calcium reabsorption. The humoral mediators involved are multiple and sometimes associated, including abnormal production of PTH-rp (parathormone related peptide), transforming growth factors, prostaglandins E-sery, Il-1 α and β or 1-25 (these factors stimulating osteoclastic resorption), dihydroxy vitamin D (elevated in certain T lymphomas or in Hodgkin’s disease). At a high rate, hypercalcemia may be responsible for acute nephrocalcinosis.
Myelomatous tubulopathy:
Acute renal failure secondary to “myeloma tubulopathy” in lymphoma with monoclonal protein, although rare, has also been reported.
Treatment Complications:
Treatment-related complications currently represent the most common causes of renal failure associated with hematological disorders. We will mainly deal with radiation nephritis and tumor lysis syndrome, the frequent complications related to the nephrotoxicity of cytotoxic drugs (cisplatin, methotrexate, nitrosoureas, etc.) are developed in another chapter.
Radical nephritis:
Despite the widespread use of radiotherapy in the treatment of certain blood disorders, the frequency of radiation nephritis has decreased significantly over the past 10 years due to better protection of renal areas. Renal lesions of the glomerular or more often interstitial type are generally observed after irradiation greater than 2,300 rads.Symptoms appear 6 to 12 months after radiotherapy. Proteinuria and arterial hypertension are the first signs described, kidney failure being of late appearance and slow evolution.
Tumor lysis syndrome:
Tumor lysis syndrome (TLS) is the result of the massive destruction of tumor cells by effective chemotherapy resulting in the release of intracellular content in the extracellular space. It can exceptionally be spontaneous and revealing of the disease. The biological syndrome associates four cardinal disorders: hyperkalemia, hyperuricemia, hyperphosphaturia and hypocalcemia, to which can be added renal insufficiency. The frequency of SLT depends on the treated neoplasia, Burkitt’s lymphoma being the most frequently cited. This impact is difficult to estimate and vary depending on the definition chosen. Thus, in the case of NHLs, if the SLT criteria are only biological and relatively undemanding (25% variation of two of the four cardinal signs), the frequency is estimated at 42%. On the other hand, if more stringent criteria are chosen (serum potassium> 6 mEq / L, serum creatinine> 221 mmol / L, calcemia <1.5 mmol / L, cardiac arrhythmia or death), the frequency drops to 6%. In Burkitt’s lymphoma, in 37 patients with 46 chemotherapy, urea elevation was observed in 30% of cases, hyperphosphoremia and hypocalcemia in more than 50% of cases, hyperkalemia and hyperuricemia in 9%. cases.
Hyperkalemia:
Hyperkalaemia generally precedes other biological signs due to early alteration of ATPases by chemotherapy before cell lysis itself. ATPases no longer maintain potassium in the cell against the intra-extracellular concentration gradient Sudden hyperkalemia poses the risk of cardiac rhythm or cardiac conduction and sudden death, especially if associated with acidosis and / or hypocalcemia.
Hyperphosphoremia and hypocalcemia:
Lysis of tumor cells releases large quantity of nuclear material (DNA [deoxyribonucleic acid] and RNA [ribonucleic acid]) rich in phosphates in the extracellular sector. Acute hyperphosphoremia exceeds the possibility of renal excretion all the more easily as the renal function is first altered.
Hypocalcemia is a direct consequence of hyperphosphatemia.
Uric nephropathy:
It corresponds to acute oligoanuric renal failure syndrome associated with elevated levels of plasma uric acid and the appearance of uric acid crystals in the urine. Uric acid is the final product of human purine degradation in humans.During tumor lysis, nucleotides rich in purines are released in the extracellular sector. The purines are then metabolized to hypoxanthine, then to xanthine, and finally to uric acid. The freely circulating uric acid is filtered by the glomerulus and undergoes reabsorption and secretion processes in the proximal tube at the end of which about 10% of the filtered fraction is excreted.
The major hyperruricemia (> 1000 μmol / L) secondary to the tumor lysis then exposes a risk of precipitation which will depend essentially on the intratubular pH and the tubular uric acid concentration, itself dependent on the glomerular filtration rate. The pKa of uric acid is low, which explains why its solubility is very low in acidic urinary medium. On the other hand, at pH 7 it is 13 times more soluble, in the form of sodium urate, than at pH 5. Thus, when the urine is acidic and concentrated, a precipitation of uric acid crystals takes place in the cells. Distal tubes and collectors leading to acute renal failure. A ratio of urine concentrations of uric acid / cretinin greater than 1 would distinguish patients with acute urinary nephropathy from those whose uricemia is elevated secondary to renal failure. The treatment is essentially preventive, combining hydration and alkalization prior to the start of the treatment of hematological disorders, relying in particular on urinary pH. The systematic administration of urate oxidase allowing the metabolism of uric acid to allantoin more soluble, (Uricozyme ® ) is recommended the first days. The risk factors are related to the type of hematology, the size of the tumor mass, the supposed effectiveness of treatment, possible renal failure and a high concentration of LDH or uric acid.
To a lesser degree, excessive production of uric acid may be responsible for the formation of uric lithiasis.
In patients treated in the long term by a xanthine oxidase inhibitor such as allopurinol, the formation of crystals of xanthine and oxypurinol is possible and then also responsible for a lithiasis pathology.
CONCLUSION:
The review of these renal disorders related to mainly lymphoid hemopathy allows to emphasize a certain number of observations. Recent data from the literature establish, in a large number of cases, the paraneoplastic character of most glomerulopathy associations with lymphoid hemopathy whose frequency is still probably underestimated. This link is of obvious clinical interest as nephropathy often reveals hematological disease or accompany relapse. In addition, as we have seen, the specific treatments for hematological diseases are also effective on the evolution of nephropathy. Finally, the various immunological peculiarity of these haemopathy are probably at the origin of the diversity of observed glomerular lesions, constituting for the nephrologist particularly interesting models for the analysis of the physiopathological mechanisms of nephropathy.
